ORIGINAL PAPER

Evaluation of a novel index by tissue Doppler imaging in

patients with advanced heart failure: relation to
functional class and prognosis
C.-H. Lee, F.-C. Lin, C.-C. Chen, M.-J. Hsieh, P.-C. Chang, I.-C. Hsieh, M.-S. Wen, K.-C. Hung, D. Wu

Second Section of Cardiology,

Department of Internal
Medicine, Heart Failure Center,
Chang Gung Memorial Hospital,
Chang Gung University College
of Medicine, Taipei, Taiwan
Correspondence to:
Kuo-Chun Hung, MD, Chang
Gung Memorial Hospital, 199
Tung Hwa North Road, Taipei,
105 Taiwan
Tel.: + 2 886 3 3281451
Fax: + 2 886 3 3281451
Email: hkuo.chun@gmail.com
Disclosures
None.
SUMMARY
What’s known
Background: Despite the ability of tissue Doppler imaging (TDI) to detect left ven- Previous studies have established the relationship
tricular (LV) systolic and diastolic myocardial functions in patients with heart fail- between clinical features and conventional
ure, the added value of TDI to clinical variables and conventional echocardiography echocardiographic indices in patients with heart
failure. The EAS index derived from tissue Doppler
in predicting the symptoms and outcome of advanced heart failure has not been
imaging, which reflects combined systolic and
clearly defined. Methods and results: Two hundred and thirty adult patients
diastolic performance is associated with cardiac
diagnosed with congestive heart failure were assigned to study groups based on mortality and preclinical dysfunction in the general
the New York Heart Association functional classes. Pulsed-wave TDI (PWTDI), population. The added value of tissue Doppler
including average of peak systolic (Sm), early (Em) and late diastolic (Am) veloci- imaging to clinical variables and conventional
ties from six mitral annular sites was evaluated. PWTDI was also calculated to cre- echocardiography in predicting the symptoms and
ate a combined index (EAS index) of diastolic and systolic performances. All outcome of heart failure has not been clearly
patients were followed up for cardiac-related death and hospitalisation as a result defined.
of heart failure. Patients with functional class III–IV had a significantly higher EAS
What’s new
index (0.21 ± 0.19 vs. 0.13 ± 0.08, p < 0.05) than those with class I–II and the
The EAS index is a highly effective means of
control (0.10 ± 0.04, p < 0.05). Except for Sm and Em, all conventional echocar- differentiating between patients with functional
diographic Doppler parameters and TDI variables significantly correlated with func- class I-II and those with III-IV. It also correlates
tional class. Moreover, according to multiple stepwise analysis, EAS index and with cardiac mortality and hospitalisation for
percentage of chronic renal insufficiency (CRF) were the only two independent pre- worsening heart failure, thus providing additional
dictors of functional class (EAS index, p = 0.006; CRF, p = 0.019). During follow- value.
up (median, 30 months), 93 participants had cardiac events. EAS index, LV mass
index and CRF were significant predictors of cardiac mortality and hospitalisation
[EAS index, hazard ratio (HR) 4.962, p = 0.006; LV mass index, HR 1.007,
p = 0.003; CRF, HR 1.616, p = 0.040]. Conclusions: The EAS index, which
reflects systolic and diastolic performances, is a highly effective means of differenti-
ating between patients with functional class I–II and those with III–IV. The index
also correlates with cardiac mortality and hospitalisation for worsening heart fail-
ure, thus providing additional value to conventional echocardiographic measures.

Among the several factors that affect the mitral

Introduction
Heart failure refers to either the severity of cardiac
dysfunction or the status of the impaired function.
The New York Heart Association (NYHA) classifica-
tion is extensively adopted to evaluate the functional
status of heart failure, which depends mainly on
symptoms during exertion. As it is well known,
decreased functional capacity is an important symp-
tom of chronic heart failure (CHF). Previous studies
have established the relationship between clinical fea-
tures in patients with left ventricular (LV) dysfunc-
tion and echocardiographic indices such as mitral
inflow velocities and ejection fraction (EF) (1).
inflow velocities and EF include the rate of myocar-
dial relaxation and endocardial border definition
(2–4).
Compared with mitral inflow velocity profiles and
EF, tissue Doppler imaging (TDI) is a relatively pre-
load independent echocardiographic modality, which
quantifies directly myocardial diastolic and systolic
wall motion velocities throughout the full cardiac
cycle (5). TDI is also a non-invasive means of evalu-
ating LV regional and global functions based on a
high frame rate that surpasses human visual capabili-
ties and depends less on image quality than conven-
tional echocardiography (6).

ª 2011 Blackwell Publishing Ltd Int J Clin Pract, August 2011, 65, 8, 852–857
852 doi: 10.1111/j.1742-1241.2011.02699.x

Tissue Doppler imaging variables, including sys-
tolic (Sm), early (Em) and late (Am) diastolic mitral
annular velocities, were found to correlate well with
LV systolic and diastolic function (7). The correla-
tion of TDI parameters with clinical functional status
and prognosis has seldom been addressed (1). The
EAS index, which reflects combined systolic and dia-
stolic performance, is associated with cardiac mortal-
ity and preclinical dysfunction in the general
population (8). To our knowledge, this parameter
has not been evaluated in patients with a significant
amount of LV dysfunction. Therefore, this study
evaluates the relationship of mitral annular velocities
with a novel index, conventional Doppler parame-
ters, clinical symptoms and outcome in patients with
significant LV dysfunction.
Methods
Study population
The study group consisted of 230 adult patients (166
men and 64 women) who had congestive heart fail-
ure and were admitted in our hospital for evaluation
and management between 2008 and 2010. Inclusion
criteria were the presence of LVEF < 40%, sinus
rhythm and absence of significant valvular or con-
genital heart disease. Patient symptoms were evalu-
ated based on the New York Heart Association
(NYHA) functional classification. The functional
class was categorised by experienced independent
observers blinded to the echocardiographic findings.
The control group comprised 29 healthy subjects (20
men, 9 women) without signs or symptoms of heart
failure. The study protocol was reviewed and
approved by the institutional review board. Informed
written consent was obtained from each patient
before enrollment. The study was conducted accord-
ing to the rules of the Helsinki Declaration.
Conventional M-mode, two-dimensional (2D)
and Doppler echocardiography
Each subject underwent transthoracic M-mode, 2D
and Doppler echocardiography using commercially
available echocardiography units (Vivid 7, GE
Healthcare, Milwaukee, USA or Philips SONOS
7500, Best, The Netherlands). The LV end-diastolic
volume index (LVEDVI), LV end-systolic volume
index (LVESVI) and LVEF were evaluated in apical
two-chamber and four-chamber views using modi-
fied Simpson’s rule. Transmitral early (E) and late
(A) diastolic flow velocities, deceleration time (DT)
of early diastolic flow velocity, isovolumic relaxation
time (IVRT) and myocardial performance index
(MPI) were determined using conventional Doppler
echocardiography.
ª 2011 Blackwell Publishing Ltd Int J Clin Pract, August 2011, 65, 8, 852–857
New index relates to prognosis of heart failure 853
Pulsed wave tissue Doppler imaging
In each patient, pulsed wave tissue Doppler imaging
(PWTDI) was performed immediately after conven-
tional echocardiography. TDI of the mitral annulus
was obtained at six sites from the apical four-cham-
ber, two-chamber and long axis views. A combina-
tion of transmitral flow velocity with annular
velocity (E ⁄ Em) was also estimated for evaluating the
LV filling pressure. These variables were analysed
individually as the average of six sites of annulus.
Ratios of Em ⁄ (Am · Sm) (EAS index) were esti-
mated as measures of combined systolic and diastolic
performances.
The velocity time integral acquired by PWTDI
during expiration phase was recorded and stored on
videotape, digitalised and transferred to a digital-
video disc for off-line analysis. At least three end-
expiratory beats were evaluated, with their average
values obtained as well.
Reproducibility of measurements
Ten patients were selected to determine the repro-
ducibility of the measurements by two independent
observers for inter-observer variability and by the
same observer on two separate occasions for intra-
observer variability. Variability was determined as
the difference between the two sets of measurements
divided by the mean of the measurements, as
expressed in percentage form.
Statistical analysis
Continuous variables were expressed as means ± SD,
and categorical variables were expressed as absolute
number (percentage). Exactly how the groups differ
was estimated using analysis of variance with the post
hoc test.
To predict functional class, a series of multivariate
stepwise logistic regression models was fitted to the
data. Odds ratios (OR) and 95% confidence intervals
(CI) were estimated from the model.
Univariate Cox proportional hazards were per-
formed to evaluate the significance of various vari-
ables as the predictors of cardiac death or
hospitalisation. Variables predictive of the outcome
(p < 0.1) were then entered into a multivariate Cox
proportional hazards regression models (forward
selection) to identify independent predictors of out-
comes. The output from the Cox regression analysis
is given as hazard ratios with 95% CI. Cumulative
curves for cardiac events were obtained using the
Kaplan–Meier method. All TDI parameters were
adjusted for age, baseline LVEF, gender, hypertension
and body mass index (9,10). A p £ 0.05 was consid-
ered statistically significant. spss software (version
854 New index relates to prognosis of heart failure

17.0 for Windows; SPSS Inc., Chicago, IL, USA) was
used for data analysis.
Results
Forty three patients died of cardiac causes, 48
patients were hospitalised for worsening heart failure
and two patients received cardiac transplants during
a median follow-up of 30 months.
Patient characteristics (Table 1)
Clinical characteristics of the cohort of 230 patients
were analysed. One hundred and twenty-six patients
had NYHA class I or II and 104 had class III or IV.
The two groups resembled each other with respect to
age, male gender, ischemic heart disease, diabetes
mellitus and hypertension. Notably, either the class
III or IV group contained a significantly higher per-
centage of chronic renal insufficiency (CRF) than
patients with Fc I or II. The patients took the follow-
ing medications: 188, angiotension-converting
enzyme inhibitors or angiotensin II receptor block-
ers; 198, beta-adrenoreceptor blockers; 87, spirono-
lactone.
Conventional and PWTDI echocardiography
(Table 2)
Comparing the patients with heart failure with the
control group revealed that they significantly differed
in M-mode and 2D parameters, mitral inflow veloci-
ties, MPI and TDI variables. Patients with heart fail-
ure had an equivalent degree of LV dilation such as
left atrial diameter, LVEDVI, LVESVI, as well as LV
mass index and MPI. However, the two groups only
slightly differed in LVEF (p = 0.066). A significantly
high value was noted in A, DT of E, IVRT and Am
in patients with Fc I–II. A high E, E ⁄ A ratio, E ⁄ Em
ratio and EAS index were found among the Fc III–
IV group. In addition, although the value of Em was
compatible with Fc I–II and Fc III–IV, the Sm value
indicated a borderline difference between two
groups(p = 0.077).
Relationship to NYHA classification and cardiac
outcome
As for multivariate stepwise logistic regression analy-
sis adjusted for age, baseline LVEF, gender, hyperten-
sion, as well as body mass index, EAS index and
CRF were the independent predictors of functional
class (EAS index, p = 0.006, OR 8.515, 95% CI,
1.837–39.466; CRF, p = 0.019, OR 2.253, 95% CI,
1.144–4.439).
The mortality and morbidity rate during
30 months in the study patients was 40%. All of the
variables that predicted the combined outcome of
death or hospitalisation on univariate Cox regression
analysis (p < 0.1) were entered into a forward multi-
variate Cox regression analysis. EAS index, LV mass
index and CRF emerged as independent predictors of
outcome in patient with LV dysfunction (EAS index,
hazard ratio (HR) 4.962, 95% confidence interval
(CI), 2.071–11.888, p = 0.006; LV mass index, HR
1.007, 95% CI, 1.002–1.012, p = 0.003; CRF, HR
1.616, 95% CI, 1.022–2.555, p = 0.040). Table 3 dis-
plays the final multivariate Cox model. Figure 1 illus-
trates Kaplan–Meier curves showing the patients with
heart failure categorised according to EAS index of
greater or less than 1.20 (median value).
Inter-observer and intra-observer variability
The inter-observer variability and intra-observer vari-
ability for TDI parameters were below 7%.

Table 1 Clinical characteristics

Control (n = 29) Fc I–II (n = 126) Fc III–IV (n = 104) ANOVA p values

Age (years) 63 ± 9 64 ± 14 63 ± 15 0.934

Male gender, % 20 (69) 97 (77) 69 (66) 0.192
Ischemic heart 0 (0) 67 (54) 63 (61) < 0.001* 
disease
Chronic renal 0 (0) 26 (21) 34 (33) < 0.001* à
insufficiency
Diabetes mellitus 0 (0) 69 (52) 58 (45) < 0.001* 
Hypertension 0 (0) 56 (44) 49 (47) < 0.001* 
Medications
ACEI or ARB, % 0 (0) 106 (84) 82 (79) < 0.001* 
Beta Blockers, % 0 (0) 110 (87) 88 (85) < 0.001* 
Spironolactone, % 0 (0) 48 (38) 39 (38) < 0.001* 

*Control vs. Fc I–II, p < 0.05 in post hoc analysis.  Control vs. Fc III–IV, p < 0.05 in post hoc analysis. àFc I–II vs. Fc III–IV, p < 0.05
in post hoc analysis. ANOVA, analysis of variance; ACEI, angiotensin converting enzyme inhibitor; ARB, angiotensin II receptor blocker.

ª 2011 Blackwell Publishing Ltd Int J Clin Pract, August 2011, 65, 8, 852–857
 New index relates to prognosis of heart failure 855

Table 2 Conventional two-dimensional and Doppler echocardiographic findings

Control (n = 29) Fc I–II (n = 126) Fc III–IV (n = 104) ANOVA p values

M-mode and 2-D

LA dimension (mm) 40.6 ± 5.1 45.5 ± 6.5 45.6 ± 8.2 < 0.001* 
LVEDV index (ml ⁄ m2) 57.4 ± 9.1 114.9 ± 39.9 112.5 ± 38.4 < 0.001* 
LVESV index 17.5 ± 4.6 85.3 ± 3.72 86.0 ± 36.9 < 0.001* 
(ml ⁄ m2)
LV mass index 100.1 ± 13.0 175.6 ± 63.1 177.4 ± 58.5 < 0.001* 
(g ⁄ m2)
LVEF (%) 64.5 ± 5.4 27.4 ± 7.9 25.4 ± 9.2 < 0.001* 
MPI 0.53 ± 0.11 0.85 ± 0.71 0.95 ± 0.66 0.018* 
Mitral inflow velocities
E (cm ⁄ s) 74.2 ± 12.7 77.0 ± 32.6 89.8 ± 31.0 0.003 à
A (cm ⁄ s) 84.2 ± 23.2 84.7 ± 29.4 72.5 ± 31.1 0.005à
E⁄A 0.92 ± 0.23 1.07 ± 0.78 1.57 ± 1.02 < 0.001 à
DT of E (ms) 282.5 ± 128.1 207.0 ± 82.0 168.7 ± 50.7 < 0.001* à
IVRT (ms) 91.1 ± 16.0 110.9 ± 28.8 94.5 ± 29.8 < 0.001*à
Tissue Doppler imaging
Sm (cm ⁄ s) 8.2 ± 1.4 5.1 ± 3.8 4.8 ± 1.4 < 0.001* 
Em (cm ⁄ s) 7.0 ± 1.7 4.3 ± 1.4 4.5 ± 1.5 < 0.001* 
Am (cm ⁄ s) 9.6 ± 1.8 7.0 ± 2.0 6.0 ± 2.7 < 0.001* à
E ⁄ Em 11.5 ± 5.0 18.8 ± 8.5 22.1 ± 11.0 < 0.001* à
EAS index 0.10 ± 0.03 0.14 ± 0.08 0.22 ± 0.19 < 0.001 à

*Control vs. Fc I–II, p < 0.05 in post hoc analysis.  Control vs. Fc III–IV, p < 0.05 in post hoc analysis. àFc I–II vs. Fc III–IV, p < 0.05
in post hoc analysis. A, late diastolic transmitral Doppler flow velocity; Am, late mitral annular diastolic velocity; DT, deceleration time;
E, early diastolic transmitral Doppler flow velocity; EAS, ratio of Em ⁄ (Am · Sm); EDV, end diastolic volume; EF, ejection fraction; ESV,
end systolic volume; Em, early mitral annular diastolic velocity; IVRT, isovolumic relaxation time; LA, left atrium; LV, left ventricular;
MPI, myocardial performance index; Sm, mitral annular systolic velocity.

Table 3 Univariate and multivariate predictors of cardiac death and hospitalisation

Univariate analysis Multivariate analysis

HR (95% CI) p value HR (95% CI) p value

EAS index 3.998 (1.834–8.715) < 0.001 4.962 (2.071–11.888) < 0.001*
LV mass index 1.006 (1.002–1.010) 0.002 1.007 (1.002–1.012) 0.003
Chronic renal insufficiency 1.709 (1.108–2.637) 0.015 1.616 (1.022–2.555) 0.040
Diabetes mellitus 1.547 (1.029–2.326) 0.036 NA NA
A 0.994 (0.987–1.000) 0.064 NA NA
DT 0.997 (0.994–1.000) 0.058 NA NA
IVRT 0.991 (0.984–0.998) 0.014 NA NA
E⁄A 1.244 (1.018–1.520) 0.032 NA NA
Sm 0.778 (0.609–0.991) 0.044 NA NA

*Adjusted for age, baseline LVEF, gender, hypertension and body mass index. CI, confidence interval; HR, hazard ratio; NA, not
applicable.

functional class. The EAS index also correlates well

Discussion
This study investigated the relationship of mitral
annular velocities and clinical manifestations in
patients with significant LV dysfunction, demonstrat-
ing that EAS index is the independent predictor of
with cardiac mortality and hospitalisation for heart
failure.
With its incidence having increased in recent dec-
ades, CHF is a common clinical syndrome (11).
Renal insufficiency and increased LV mass index are

ª 2011 Blackwell Publishing Ltd Int J Clin Pract, August 2011, 65, 8, 852–857
856 New index relates to prognosis of heart failure
Figure 1 Survival curves categorised according to EAS
index lesser (upper curve) or greater (lower curve) than
0.12 (median value; p < 0.001). Vertical bars represent
censored observations
common in patients with heart failure. Our results
confirm previous studies that have demonstrated that
renal impairment and LV hypertrophy are associated
with outcomes in heart failure patients with systolic
dysfunction, and that the percentage is high in those
patients with Fc III–IV (12,13).
Many patients with heart failure have a spectrum
of systolic and diastolic abnormalities. A previous
study established that exercise limitations in patients
with heart failure are related to a failure in increasing
end-diastolic volume despite a significant elevation
in filling pressures (14). The transmitral flow pattern
remains the most effective means of routinely mea-
suring diastolic function and predicting a poor prog-
nosis in patients with LV dysfunction (15,16).
Conventional echocardiographic variables of diastolic
dysfunction strongly correlated with congestive
symptoms in previous studies (1,17). Our study con-
firms diastolic function detected by mitral inflow
parameters, and congestive symptoms expressed as
functional class are directly correlated with each
other. Mitral inflow variables with the exception of
the early filling velocity also correlated with cardiac
mortality and hospitalisation for heart failure in
patients with an advanced disease.
Congestive heart failure symptoms in patients with
significant LV dysfunction are normally caused by
sub-endocardial ischemia induced by the elevated LV
filling pressure. Mitral annular velocity detected by
TDI reflects the lengthening of LV myocardial fibres
of the sub-endocardium in the longitudinal direc-
tion, and appears to be effective for assessing conse-
quences of ischemia (18). A previous study
demonstrated that Sm is a predictor of outcome in
patients with CHF and LV systolic dysfunction, and
was well-related to LV systolic function (3,7). Abe
ª 2011 Blackwell Publishing Ltd Int J Clin Pract, August 2011, 65, 8, 852–857
et al. found that decreased Am of mitral annular
velocity implies elevated pulmonary venous pressure
in patients with left heart failure (19). Troughton
et al. and Hillis et al. found that high E ⁄ Em is asso-
ciated with a poor prognosis and elevated LV end-
diastolic pressure (20,21). Our study demonstrates
that Sm and E ⁄ Em > 16 are predictors of cardiac
events. In addition, E ⁄ Em and Am are correlated to
functional status.
Em may be lower than other measurements e.g.
Sm and Am, in some patients with congestive heart
failure and disproportionate changes in patients with
regional dysfunction. The validity of this index may
be low in this condition. Thus, using TDI with the
average of annular velocity at different sites may
facilitate efforts to evaluate quantitatively global LV
function.
Previous studies reported that in contrast with
conventional Doppler indices or mitral annular
velocities alone, the EAS index correlated with prog-
nosis in large community-based population studies
(8,22). In this study, the combined variable is also an
independent predictor of functional class. In addi-
tion, cardiac mortality and hospitalisation for heart
failure in patients with significant LV dysfunction are
predicted. On the basis of our results, we speculate
that in patients with significant LV dysfunction,
markers of systolic and diastolic dysfunction corre-
late strongly with congestive symptoms. Thus, the
EAS index may add significant value to the clinical
follow-up and management of patients with heart
failure.
Study limitations
Despite its contributions, this study has several limi-
tations. NYHA functional classification is a difficult
variable to evaluate and quantify, given its rather
subjective nature. However, validity of the NYHA
functional class has been demonstrated in studies
that have reported moderate correlations with
VO2max and a strong independent prognostic
impact in a wide variety of cardiovascular clinical
settings (23). In addition, an accurate recording of
mitral annular diastolic velocity requires a parallel
alignment between the ultrasound beam and the
mitral annular sites in PWTDI. The incidence angle
may not be exactly parallel because of changes in
mitral annular geometry caused by marked dilated
LV, which was observed in some patients in this
study. Moreover, TDI is not entirely preload inde-
pendent (24). However, patients in this study did
not have a significant volume change during the
study period. Furthermore, this study excluded
patients with atrial fibrillation and significant valvu-
lar heart disease, thus excluding a substantial number
 New index relates to prognosis of heart failure 857

of patients with CHF, and possibly causing a bias in
the analytical results. Finally, no patients underwent
biopsy specimen–proven severe cardiac amyloidosis,
which is reduced myocardial velocity throughout sys-
tole and both phases of diastole, i.e. low readings of
Em, Am and Sm. However, although the EAS index
may be valid in this condition, further studies using
a patient population with amyloidosis may be war-
ranted to determine more clearly the prognostic
value because the extremely low Am increases the
EAS index (25).
Conclusions and clinical implications
The evaluation of LV dysfunction by PWTDI may
significantly contribute to efforts to evaluate and
manage patients with CHF. Conventional Doppler
indices and TDI parameters correlate with the sever-
ity of symptoms in patient with significant LV dys-
function and advanced heart failure. However, the
EAS index usefully discriminates patients with func-
tional class I–II from patients with functional class
III–IV, supporting the role of LV contractile and LV
end-diastolic pressure in producing pathophysiologi-
cal mechanism of functional impairment in these
patients. The EAS index also predicts the clinical
outcome.
Acknowledgements
The authors thank the National Science Council of
the Republic of China, Taiwan (Contract No.
NMRPG360341) and Chang Gung Memorial Hospi-
tal (Contract No. CMRPG371951) for partially sup-
porting this research. Ted Knoy is appreciated for his
editorial assistance.

Doppler imaging is an independent predictor of 18 Simpson IA. Echocardiographic assessment of long

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