Download Impact of left ventricular volume/mass ratio on diastolic function

CLINICAL RESEARCH
European Heart Journal (2009) 30, 1213–1221
doi:10.1093/eurheartj/ehp084
Heart failure/cardiomyopathy
Impact of left ventricular volume/mass
ratio on diastolic function
Adisai Buakhamsri 1,2†, Zoran B. Popović1†, Jingna Lin 1, Pascal Lim 1,
Neil L. Greenberg 1, Allen G. Borowski 1, W.H. Wilson Tang1, Allan L. Klein 1,
Harry M. Lever1, Milind Y. Desai 1, and James D. Thomas 1*
1
Division of Cardiovascular Medicine, Department of Cardiology, Desk F-15, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195, USA; and 2Faculty of Medicine,
Department of Medicine, Thammasat University, Bangkok, Thailand
Received 19 March 2008; revised 1 February 2009; accepted 18 February 2009; online publish-ahead-of-print 20 March 2009
Aims
To assess the impact of left ventricular (LV) volume/mass ratio on diastolic function parameters in subjects with
dilated cardiomyopathy (DCM) or hypertrophic cardiomyopathy (HCM) and healthy controls.
.....................................................................................................................................................................................
Methods
We performed echocardiography in 44 healthy controls, 35 HCM subjects, 29 DCM subjects with narrow QRS
and results
complex (DCM-n), and 27 DCM subjects with wide QRS complex (DCM-w). Mitral annulus velocity (Ea) and transmitral E-wave velocity were used to estimate time constant of isovolumic pressure decay (t). LV flow propagation
velocity (Vp) and early intraventricular pressure gradient (IVPG) were derived from colour M-mode of LV inflow.
We calculated LV twist and peak untwisting rate (UntwR) by speckle tracking. Mean LV volume/mass ratio was
0.34 + 0.09 mL/g in healthy controls, 0.15 + 0.06 mL/g in HCM, 0.6 + 0.2 mL/g in DCM-n, and 0.8 + 0.3 mL/g in
DCM-w patients (P , 0.001 for all groups). Resting LV ejection fractions were 63 + 7, 64 + 8, 31 + 8, and
26 + 8%, respectively (P , 0.01 vs. controls for DCM groups). In a multivariate analysis, LV volume/mass ratio
remained a strong independent predictor of Vp (P , 0.001), IVPG (P ¼ 0.009), and UntwR (P , 0.001) but not for
Ea (P ¼ 0.25).
.....................................................................................................................................................................................
Conclusion
LV volume/mass ratio had influences on diastolic function parameters independent of intrinsic diastolic function and
filling pressures. It should be considered when assessing patients suspected of LV diastolic dysfunction.
----------------------------------------------------------------------------------------------------------------------------------------------------------Keywords
Left ventricular volume/mass ratio † Diastolic function † Dilated cardiomyopathy † Hypertrophic cardiomyopathy
† Ventricular torsion (twist) † Echocardiography
Introduction
A wealth of data supports patient classification into specific diastolic dysfunction groups based on various parameters of left ventricular (LV) filling.1 – 5 This classification correlates with objective
measures of cardiovascular performance such as pulmonary capillary wedge pressure (PCWP) or the time constant of isovolumic
pressure decay6 – 10 and is also a predictor of patient’s symptoms
and survival. The classification bases on the transmitral and pulmonary vein flow profiles and on isovolumic relaxation time
(IVRT). However, the past decade introduced new markers of diastolic function that are based either on intraventricular flow or LV
wall motion.11 The need for these newer parameters was driven by
the U-shaped relationship between the ratio of early-to-late transmitral flow velocity (E/A) with filling pressure and facilitated by
technical developments in echocardiography.
Engineering insight, as well as a modelling study,12 suggests that
some new markers of diastolic function, such as colour M-mode
flow propagation velocity (Vp), are affected by LV dilation or presence of concentric hypertrophy. This implies that values of Vp
considered normal in the setting of dilated cardiomyopathy
(DCM) may be abnormal in hypertrophic cardiomyopathy
(HCM). For these reasons, we conducted a study to assess the
way diastolic function parameters behave in the presence of
* Corresponding author. Tel: þ1 216 445 6312, Fax: þ1 216 445 7306, Email: [email protected].
† The first two authors contributed equally to the study.
Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2009. For permissions please email: [email protected].
1214
altered LV volume and mass (both represented by LV volume/mass
ratio) as seen in DCM or HCM. A primary aim of this study was to
determine whether LV volume/mass ratio affects parameters of
diastolic function.
Methods
Study population
Patients
To identify patients, we first cross-referenced a list of patients for which
the echocardiography report stated the presence of hypertrophic (n ¼
810) or non-ischaemic DCM (n ¼ 940) with a database of 12 768 Cleveland Clinic patients in whom echocardiography was performed on a Vivid
7 ultrasound machine (GE Medical, Milwaukee, WI, USA) in a period of
January 2004–December 2007. The medical records were then
checked to ascertain that inclusion criteria were satisfied as follows.
HCM was diagnosed by the echocardiographic demonstration of a hypertrophied, non-dilated LV in the absence of other acquired or congenital
heart disease. Non-ischaemic DCM was diagnosed in a presence of
dilated left ventricle with ejection fraction ,40%, no prior history of
myocardial infarction, and no significant coronary artery stenosis on coronary angiography. DCM subjects were subcategorized according to QRS
width into DCM with narrow QRS (,130 ms, DCM-n) or DCM with
wide QRS (130 ms, DCM-w). Finally, patients were selected if acquired
echocardiography study was of a satisfactory quality (35 from 55 HCM
subjects, 29 from 40 DCM-n subjects, and 27 from 46 DCM-w subjects)
as indicated in Data acquisition section.
All patients were clinically stable and in normal sinus rhythm.
Patients were excluded for significant valvular heart disease (mitral
regurgitation was allowed if it was less than moderate degree), pacemaker implantation, prior cardiac surgery, or percutaneous LV septal
reduction procedure. According to aforementioned criterions, all
patients were identified (n ¼ 94, age 53 + 14 years, range 22 – 79
years).
Control subjects
Our healthy controls were selected from our database of 102 normal
subjects. These subjects volunteered for an echocardiography study
after being informed through information panels located throughout
Cleveland Clinic main campus. Subjects were declared healthy after
normal electrocardiogram and thorough medical history and physical
examination (including testing of fasting blood glucose and cholesterol
fraction levels) revealed no cardiovascular disease. None of them
reported taking cardiac medications (except aspirin). To assess the
impact of aging on diastolic function, we first randomly sampled
healthy controls out of this population (n ¼ 74, average age 41 + 15
years, range 18 – 76 years). This sample size yields a two-sided
power (beta) of 80% to detect a correlation of 0.325 or greater at
the alpha level of ,0.05. To assess the differences in diastolic function
between healthy controls and patients with cardiomyopathy, we agematched these two groups. For this purpose, we sub-sampled our
74 healthy controls by, first, limiting the selection by having the age
range identical to the age range of patient sample, and then drawing
all possible samples with the size of n . 40 subjects. The selected
sample had a closest mean and SD to the patients’ sample (n ¼ 44,
age 50 + 13 years, range 22 – 76 years, P¼n.s. for the comparison
between patients and controls).
Institutional Review Board of Cleveland approved for the database
search. All subjects gave written informed consent for the participation
in respective prospective studies.
A. Buakhamsri et al.
Data acquisition
Transthoracic two-dimensional echocardiography was performed with
a Vivid 7 ultrasound machine (GE Medical Systems, Milwaukee, WI,
USA) and M3S/M4S probe. Standard views, including apical fourchamber, apical two-chamber, apical long-axis, and parasternal longand short-axis views, were obtained. Short-axis views were acquired
at the mitral valve and apical LV levels (absence of right ventricle
and papillary muscle for apical short-axis). Second-harmonic images
were acquired with high frame rate B-mode scans (40– 90 frames/s)
for speckle tracking imaging. Pulsed-wave Doppler interrogation of
the transmitral flow and LV outflow tract (LVOT), and colour
M-mode of intraventricular filling were acquired from apical fourchamber view. Two-dimensional tissue Doppler image followed by
pulsed-wave assessment of the septal and lateral mitral annulus (Ea)
were also obtained in the apical four-chamber view. All images were
stored in a digital cine-loop format for off-line analysis.
Data analysis
LV end-diastolic and end-systolic volumes, ejection fraction, and left
atrial end-systolic volume were calculated by a modified Simpson’s
biplane method from apical imaging planes. LV mass was calculated
by the area– length formula recommended by the American Society
of Echocardiography.13 LV transverse diameter in end-systole was calculated from the LV short-axis area at papillary muscle level using
equation LV diameter¼22(LV area/3.14)0.5. All cardiac chamber
volumes and mass measures were indexed to body surface area. We
assumed that LV volume at the beginning of filling (i.e. at the end of
isovolumic relaxation) could be represented by end-systolic volume.
Thus end-systolic volume/mass ratio was taken to represent a
feature of LV geometry at the beginning of LV filling.14
Peak velocity of early (E) and late (A) wave of transmitral flow and
E-wave deceleration time (DT) were measured from the pulsed-wave
Doppler obtained at the tip of mitral leaflets. Aortic valve closure and
mitral valve opening times were obtained from pulsed-wave Doppler
signal properly positioned at LVOT to calculate LV IVRT. We
derived two parameters of intraventricular filling, flow propagation velocity (Vp), and the peak early diastolic intraventricular pressure gradient (IVPG), from colour M-mode at LV inflow.15 Ea was the average of
septal and lateral annulus velocities. All values were averaged from
three cardiac cycles.
Rotational rates of the LV base and apex were measured from
short-axis echocardiographic images by speckle tracking (EchoPac
PC software, GE Medical) as described previously.16 In brief, the
instantaneous difference of basal and apical rotational rates was calculated, yielding the twisting rate (TwR) curve. Peak TwR and untwisting
rate (UntwR) were then defined by peak positive and negative values,
respectively. Twist was the peak value obtained by temporal integration of TwR curve. Two cardiac cycles of both basal and apical
data were analysed and the data were averaged.
The time constant of isovolumic pressure decay with a zero asymptote assumption (t0) was estimated using the following equation:17
t0 (ms) ¼
IVRT
lnðPÞ lnðPCWPÞ
where P is systolic blood pressure and PCWP is mean PCWP.9,18 In
HCM subjects with LVOT obstruction, peak LV systolic pressure was
estimated by adding the peak LVOT gradient to sphygmomanometric
systolic blood pressure. Mean PCWP was estimated by averaging
PCWP obtained by two previously described estimation methods
(i.e. E/Vp and E/Ea)7,8,19 to increase the accuracy of the estimation.
1215
Impact of LV volume/mass ratio on diastolic function
Table 1 Clinical and echocardiographic findings of all subjects
Control (n 5 44)
HCM (n 5 35)
DCM-n (n 5 29)
DCM-w (n 5 27)
P-value
...............................................................................................................................................................................
Age (year)
50 + 13
47 + 14
54 + 12
59 + 12§*
0.001
Male (n)
HR (b.p.m.)
16
68 + 11
24
58 + 11
19
75 + 16§‡
18
72 + 13§‡
0.01
0.002
SBP (mmHg)
120 + 14
124 + 18
115 + 21
114 + 18
0.07
DBP (mmHg)
NYHA class
69 + 9
1
73 + 12
2 + 0.4
68 + 14
2.5 + 0.6
70 + 13
2.5 + 0.6
0.3
0.001
LVESV (mL)
32 + 11
38 + 17
127 + 61*†
103 + 37
64 + 7
†
LVEDV (mL)
LVEF (%)
LVMI (gm/m2)
LV volume/mass ratio (mL/gm)
QRS width (ms)
86 + 24
63 + 7
60 + 32
0.32 + 0.09*
90 + 18
179 + 73*
31 + 8*†
178 + 98*†}
,0.001
235 + 119*†}
26 + 8*†
,0.001
,0.001
119 + 39
112 + 22
110 + 28
,0.001
0.16 + 0.06*
108 + 22
0.60 + 0.20*
106 + 12
0.80 + 0.30*
156 + 18*†}
,0.001
,0.001
DCM-n(-w), dilated cardiomyopathy with narrow(wide) QRS complex width; DBP, diastolic blood pressure; HCM, hypertrophic cardiomyopathy; NYHA, New York Heart
Association functional classification; LVEDV, left ventricular end-diastolic volume; LVEF, left ventricular ejection fraction; LVESV, left ventricular end-systolic volume; LVMI, left
ventricular mass index; SBP, systolic blood pressure.
Last column represents overall significance level by the analysis of variance. Post hoc multiple group comparisons are shown as: *P,0.001 vs. control; §P , 0.05 vs. control; †P ,
0.001 vs. HCM; ‡P , 0.05 vs. HCM; }P , 0.05 vs. DCM-n.
Table 2 Important diastolic parameters in each group of subjects
Control (n 5 44)
HCM (n 5 35)
DCM-n (n 5 29)
DCM-w (n 5 27)
P-value
...............................................................................................................................................................................
E-wave velocity (cm/s)
E/A ratio
DT (ms)
Vp (cm/s)
IVPG (mmHg)
Ea (cm/s)
71 + 17
1.3 + 0.5
80 + 21
1.4 + 0.6
76 + 26
1.8 + 1.5
82 + 32
1.6 + 1.2
0.8
0.6
204 + 42
231 + 70
173 + 61†
167 + 68†
,0.001
60 + 16
1.5 + 0.6
†
37 + 9*
1.0 + 0.4*†
35 + 12*†
1 + 0.4*†
,0.001
,0.001
7.1 + 2.7*†
5.5 + 1.9*†
5.3 + 1.4*†
,0.001
62 + 13
1.4 + 0.5
11.0 + 2.4
†
Untwisting rate (8/s)
t0 (ms)
113 + 48
35.6 + 9.2
93 + 55
42.9 + 12.0*†
48 + 30*
56.3 + 18.0*†
21 + 15*†
65.5 + 19.1*†
,0.001
,0.001
LAVI (mL/m2)
19.0 + 6.8
29.8 + 9.4*
37.4 + 17.7*
37.5 + 15.6*
,0.001
E, early transmitral inflow velocity; E/A ratio, ratio of early-to-late transmitral flow velocity; DT, deceleration time; Vp, mitral flow propagation velocity; IVPG, early diastolic
intraventricular pressure gradient; Ea, averaged mitral annulus velocity; t0, time constant of isovolumic pressure decay with a zero asymptote assumption; LAVI, left atrial volume
index.
Other abbreviations and significance as in Table 1.
To assess the accuracy of t0 estimation, we additionally analysed the
data from a prospective study of echocardiography during acutely
decompensated systolic heart failure, in which filling pressures were
routinely monitored by a pulmonary artery catheter. From this
study, we randomly selected 34 subjects (16 of whom with DCM)
with 56 echocardiography studies performed within 30 min of
PCWP measurement. We used these data to compare t0 calculated
using measured PCWP vs. t0 estimated from echocardiography only
data. We also identified nine of our patients with HCM had filling
pressures measured invasively within 48 h of echocardiography,
without any change of cardioactive medications in the meantime.
The correlation of t0 estimated by echocardiography with t0 calculated
from invasively recorded filling pressures had an of r ¼ 0.70, P ,
0.0001 (r ¼ 0.71 for systolic heart failure subjects and r ¼ 0.84 for
HCM patients), while the average difference between two methods
was 0.24 ms [95% confidence interval (CI) 22.76 to 3.24] with 95%
limits of agreement (LOA) 223.56 ms (95% CI 218.7 to 228.46)
to 24.04 ms (95% CI 18.9– 29.1). Taken together, these data imply
that our t0 estimate is physiologically relevant even with PCWP estimation error.
Validation of LV mass estimation by echocardiography
We already validated estimation of LV mass by echocardiography using
magnetic resonance imaging as a ‘gold standard’ in 16 healthy controls.20 We further assessed 10 HCM patients (eight with asymmetric
septal hypertrophy, one with concentric HCM, and one with proximal
septal bulge, mean age 30 + 9 years) and seven patients with DCM (all
with EF , 40%, mean age 57 + 20 years), all of whom had a magnetic
resonance imaging and echocardiography studies performed within 7
days. In a total group of 33 patients, a bias between two methods
was 9.7% (95% CI 21 to 21%), with 95% LOA of 222% (95% CI
241 to 23%), and 42% (95% CI 23 – 61%). Specifically, it was 6.5%
1216
A. Buakhamsri et al.
Figure 1 Examples of LV diastolic function from each group of subjects. While pulse-wave Doppler (PW) of the LV inflow in all three patient
groups shows a pattern of delayed relaxation (first row), flow propagation by CMM of the LV inflow (second row), corresponding IVPG (third
row,*), and UntwR (fourth row, arrow) were close to normal in HCM subject, but depressed in DCM subjects. In contrast, Ea was depressed in
all diseased subjects. Tracings are timed to the electrocardiogram (ECG) that appears in a lowest panel.
(95% LOA of 226 to 39%) in HCM subjects and 20% (95% LOA of
217 to 57%) in DCM subjects (see Supplementary material online,
Figure S1).
Reproducibility
To assess intra- and inter-observer variability of LV volumes and mass,
nine randomly chosen data sets (corresponding to 5% of our study
population) were measured twice, after a time interval of .1 month,
by the same observer and, at that time, also by a second observer
blinded to the measurements of the first observer. Inter- and
intra-observer variabilities were quantified as the difference and
percent difference (with a denominator a mean of the two measurements) between the two measurements along with their 95%
LOA.21 Intra-observer variability for LV end-diastolic volume, endsystolic volume, and mass was 0.9 mL (95% CI 29 to 7 mL) [95%
LOA 219 mL (95% CI 235 to 25 mL) to 17 mL (95% CI 3 –
31 mL)], 0.5 mL (95% CI 23 to 4 mL) [ 95% LOA 221 (95% CI
245 to 3 mL) to 22 mL (95% CI 22 to 46 mL)], and 2.5 g (95%
CI 219 to 24 g) [95% LOA 230 (95% CI 268 to 8 g) to 35 (95%
CI 23 to 73 g)]. For the same three parameters, percent
intra-observer variability was 0.2% (95% CI 22.7 to 2.3%) [LOA 24
(95% CI 28 to 0%) to 3% (95% CI 0 – 8%)], 0.5% (95% CI 23.2 to
4.2%) [95%LOA 25 (95% CI 211 to 1%) to 6% (95% CI 0 – 12%)],
and 20.1% (95% CI 22.7 to 2.5%) [95% LOA 24 (95% CI 29 to
1%) to 4% (95% CI 21 to 8%)]. Inter-observer variability for LV enddiastolic volume, end-systolic volume, and mass was 7.8 mL (95% CI
219 to 35 mL) [95% LOA 233 (95% CI 280 to 14 mL) to 49 mL
(95% CI 2 to 96 mL)], 22.3 mL (95% CI 29 to 5 mL) [95% LOA
213 (95% CI 225 to 21 mL) to 8 mL (95% CI 24 to 20 mL)],
and 25 g (95% CI 222 to 12 g) [95% LOA 231 g (95% CI 261 to
21 g) to 21 g (95% CI 29 to 51 g)]. For the same three parameters,
percent inter-observer variability was 1.3% (95% CI 21.9 to 4.5%)
[LOA 24 (95% CI 29 to 2%) to 6% (95% CI 0 – 12%)], 20.7%
(95% CI 23.0 to 1.6%) [95%LOA 24 (95% CI 28 to 0%) to 3%
(95% CI 21 to 7%)], and 20.5% (95% CI 22.6 to 1.6%) [95% LOA
24 (95% CI 27 to 0%) to 3% (95% CI 21 to 6%)] (see Supplementary material online, Figure S2).
Statistical analysis
Values are shown as mean + SD or percentage when appropriate.
Between– group comparisons for individual parameters were done
by analysis of variance followed by post hoc Tukey Honest Significant
Difference test to correct for multiple comparisons. Correlation
between diastolic parameters (Vp, IVPG, Ea, UntwR, and DT) and LV
volume/mass ratio was performed by simple linear regression. We
also assessed within– group correlations between diastolic parameters
and LV geometry by analysis of covariance, with patient groups as an
independent predictor and LV volume/mass ratio as a covariate.
Echocardiographic parameters of early diastolic function are affected
by preload and relaxation. Since transmitral E-wave velocity is fully
determined by preload and relaxation and t0 is a direct measure of
relaxation, we postulated that by correcting for transmitral E-wave velocity and t0 we would eliminate effects of preload and relaxation on
echocardiographic diastolic function parameters.22,23 Therefore, to
1217
Impact of LV volume/mass ratio on diastolic function
Figure 2 Correlation between LV volume/mass ratio and diastolic parameters derived from LV wall motion and intraventricular flow. Correlation between LV end-systolic volume/mass ratio (LV volume/mass ratio) and flow propagation velocity (Vp; panel A), early diastolic intraventricular pressure gradient (IVPG; panel B), averaged early diastolic mitral annulus velocity (Ea; panel C), and peak untwisting rate (UntwR; panel
D), are shown.
further study the interaction between preload, relaxation, and LV
volume/mass ratio on diastolic function we performed a multiple
regression using transmitral E-wave velocity, t0, and LV volume/mass
ratio (with variance stabilized by taking a cubed root) as predictors.
As dependent variables, we tested following five diastolic parameters
of interest: Vp, IVPG, Ea, UntwR, and DT. Then, using regression analysis results, we corrected each diastolic parameter of interest for the
values of transmitral E-wave velocity and t0 by equation:
corrected diastolic parameteri ¼
measured diastolic parameteri ðEi Eaverage ÞbE ðti taverage Þbt
Here, E is E-wave velocity, t is t0, and bE and bt are corresponding
regression coefficients, while subscript i denotes values of individual
patient. Linear regression of these corrected diastolic parameters
with LV volume/mass ratio is identical to partial correlation data
obtained from multiple linear regressions. A two-sided P-value of
,0.05 was considered statistically significant for all tests, except for
the results of linear regression analyses where P , 0.01 was considered significant to correct for multiple comparisons (n ¼ 5)
between LV volume/mass ratio and diastolic parameters.
Results
Subjects’ clinical characteristics and basic echocardiographic findings were presented in Table 1. In HCM patients, the hypertrophy
type was concentric in 15, asymmetric septal in 14, and septal
bulge in six patients (four of which had also distal septal and/or
posterior wall hypertrophy). Eleven HCM patients had resting
LVOT gradient 30 mmHg (range 33 –115), with its magnitude
correlating with LV mass (r ¼ 0.54, P ¼ 0.0008). Of note, LV
volume mass ratio correlated strongly with LV end-systolic transverse diameter (r ¼ 0.85, P , 0.0001), a more traditional parameter of LV size.
Diastolic echocardiographic parameters in each group of subjects are shown in Table 2. Although transmitral E-wave velocity
and E/A ratio were similar across the groups, all other diastolic parameters showed significant between –group differences. Examples
of some important parameters from a representative case in each
group of subjects were depicted in Figure 1.
Effect of left ventricular volume/mass
ratio on diastolic function
LV volume/mass ratio showed significant inverse relationship with
unadjusted Vp, IVPG, Ea, and UntwR (Figure 2). As LV volume/mass
ratio showed small variance within each patient group (Table 1),
only UntwR showed significant within –group correlation with LV
volume/mass ratio (r ¼ 20.28, P ¼ 0.002).
After adjusting for the impact of E and t0 by multiple regressions,
LV volume/mass ratio remained a strong independent predictor of
Vp, IVPG, UntwR, and DT (P 0.001 for all) (Table 3 and Figure 3).
In contrast, LV volume/mass ratio did not influence Ea.
1218
A. Buakhamsri et al.
Table 3 Linear regression models for predicting diastolic parameters of interest
Diastolic parameters
Predictors
Multiple R
b-Standardized
coefficients (95% CI)
P-value
...............................................................................................................................................................................
Vp
0.71
E
0.29 (0.16 to 0.42)
t0
LV volume/mass ratio
IVPG
,0.001
20.40 (20.55 to 2026)
20.36 (20.50 to 20.21)
,0.001
,0.001
0.46 (0.31–0.60)
20.26 (20.42 to 20.11)
,0.001
0.005
20.26 (20.42 to 20.10)
0.009
0.61
E
t0
LV volume/mass ratio
UntwR
0.67
E
20.02 (20.17 to 0.13)
t0
LV volume/mass ratio
20.34 (20.51 to 20.18)
0.81
,0.001
20.35 (20.52 to 0.18)
0.001
E
20.27 (20.42 to 20.12)
0.001
t0
LV volume/mass ratio
20.21 (20.38 to 20.04)
20.33 (20.50 to 20.16)
0.009
,0.001
0.17 (0.03–0.32)
20.59 (20.74 to 20.42)
0.02
,0.001
0.01 (20.15 to 0.17)
0.93
DT
0.54
0.66
Ea
E
t0
LV volume/mass ratio
CI, confidence interval; DT, early diastolic deceleration time of left ventricular inflow; E, early transmitral inflow velocity; Ea, averaged early diastolic mitral annulus velocity; IVPG,
early diastolic intraventricular pressure gradient; t0, time constant of isovolumic pressure decay with a zero asymptote assumption; UntwR, peak untwisting rate, and Vp,
transmitral flow propagation velocity.
As a resting LVOT gradient in HCM may indicate a presence of
asymmetric hypertrophy, we repeated analysis after excluding 11 subjects with resting LVOT gradient of .30 mmHg. In this setting, LV
volume/mass ratio was again a strong independent predictor of Vp
(partial r ¼ 20.47, P , 0.0001), IVPG (partial r ¼ 20.34, P ¼
0.0001), UntwR (partial r ¼ 20.44, P , 0.0001), and DT (partial
r ¼ 20.36, P ¼ 0.0001). It also had a weak impact on Ea (partial
r ¼ 20.19, P ¼ 0.03), probably reflecting a decreased sample size
in the lower portion of distribution of LV volume/mass ratio values.
Effects of ageing
In a group of 74 healthy controls, age was inversely correlated with
LV volume/mass ratio (r ¼ 20.33, P ¼ 0.004), indicating expected
association of aging and concentric remodelling. To assess if
senescence affects diastolic parameters independently of the
changes in load and relaxation that may occur concomitantly
with increasing age, we performed a multiple regression analysis
of the impact of age, E, t, and LV volume/mass ratio on
diastolic parameters. After controlling for other independent predictors, age did not independently affect Vp, IVPG, DT, and UntwR
(P ¼ n.s. for all four), whereas it correlated inversely with Ea
(partial r ¼ 20.53, P , 0.0001). Furthermore, in the same analysis,
volume/mass ratio showed a weak correlation with corrected Ea
(partial r ¼ 0.27, P ¼ 0.02), but showed inverse correlation
with corrected UntwR (partial r ¼ 20.45, P,0.0001), with a
trend towards inverse correlation with corrected Vp and IVPG
(partial r ¼ 20.22 P ¼ 0.07 and partial r ¼ 20.17, P ¼ 0.15,
respectively).
Discussion
Previous studies have shown that Vp, IVPG, Ea, and UntwR are
strongly influenced by relaxation rate10,18,24 and displayed
weak to moderate preload sensitivity.18,25 – 29 Here, we show
that Vp, IVPG, UntwR, and DT were independently influenced
by LV volume/mass ratio. In contrast, Ea was influenced by
relaxation and preload only. In practical terms, these data
indicate that depressed values of Vp, IVPG, and UntwR when
observed in HCM reflect deeper abnormalities in relaxation than
in DCM.
Computer modelling has shown that, in a normal ventricle, a
doughnut-shaped vortex forms around the column of mitral
inflow and then travels downward towards the apex.30 Increased
LV size in DCM should increase vortex size because of a larger distance between blood column and LV walls. Large vortices dissipate
energy that results in a loss of velocity of flow column. Baccani
et al.12 used fluid dynamics model of DCM to prove that LV
dilation indeed decreases Vp. Furthermore, they have shown that
this is associated with the initial vortex staying attached to the
mitral valve. Although they have not assessed IVPG, it can be surmised that it also decreases. By analogy, effects of LV volume/mass
ratio in HCM should be opposite, because boundary effects of LV
Impact of LV volume/mass ratio on diastolic function
1219
Figure 3 Correlation between LV volume/mass ratio and corrected diastolic parameters derived from LV wall motion and intraventricular
flow. Abbreviations and layout as in Figure 2. Each of the four presented diastolic parameters was corrected for the values of transmitral E-wave
velocity and tau0 (t0) using multiple regression equation data as marked by asterisk (*). R- and P-values represent the values of partial correlation from multiple regressions.
do not allow energy dissipation. Here, we corroborate that parameters of intraventricular filling, Vp, and IVPG, are indeed
decreased in DCM but frequently preserved in HCM (Table 2).
LV volume/mass ratio had influence on UntwR but not Ea,
although they both represent early diastolic wall motion
(Figure 3). The impact of LV volume/mass ratio on UntwR can be
explained through its link with LV twist. LV twist is generated
because subepicardial myocytes, oriented in a left-handed helix,
have a lever advantage over subendocardial myocytes that run in
a right-handed helix.31 As ventricles with HCM have a larger distance between endo- and epicardial layers, the subepicardial
helix becomes even more dominant,31 twisting more forcefully
the apex in the counterclockwise and the base in the clockwise
direction.32 This increased twist allows for higher peak UntwRs.
Thus, despite the fact that HCM is characterized by prolonged
time to peak UntwR and worsened relaxation33 which both
decrease UntwR, this is offset by larger LV thickness, leading to
higher UntwR than in DCM assuming similar level of relaxation
impairment. In contrast, it is puzzling that LV volume/mass ratio
does not influence Ea velocity. The presence of LV hypertrophy,
independent of whether it is concentric (as in HCM) or eccentric
(as in DCM), is sufficient to decrease Ea.
Another factor that can influence diastole is intraventricular
conduction delay (IVCD) as represented by QRS width. IVCD
may lead to dyssynchronous relaxation of LV regions by increasing
dispersion of repolarization. However, in DCM, IVCD is predictive
of disease severity,34,35 and thus it is difficult to dissociate effects of
IVCD from that of severe DCM. Our study indicated that, while
diastolic function parameters worsen with a degree of IVCD in a
univariate analysis, after adjustment for LV volume/mass ratio, a
loss of diastolic suction and ventricular recoil in DCM was independent of the presence of IVCD.
Clinical implications and future directions
Although new diastolic function parameters are being proposed
continuously, only Ea and Vp have been tested for their prognostic
value. Some studies showed that Ea has incremental predictive
power over and above clinical and standard echocardiography
data,36,37 our group, albeit in a smaller study, failed to confirm
the predictive value of either Ea or Vp.38 On the other hand, prognostic value of Ea and Vp improves once they corrected for E-wave
velocity.38,39 Our data imply that Vp, as well as IVPG, UntwR, and
DT, have to be additionally corrected for underlying LV geometry.
These findings are especially relevant, if clinical trials are planned to
test these diastolic parameters.
An obstacle for a wider use of diastolic parameters, we assessed
here is that they can be generated only by complex and timeconsuming post-processing. Currently, only Ea can be readily
1220
derived from most ultrasound machines. However, this obstacle
could be easily overcome, if the manufacturers of echo devices
incorporate post-processing algorithms into standard ultrasound
machines. Given a current level of development, this should be a
simple engineering feat.
Limitations
We have not assessed LV volumes and mass using threedimensional methods such as magnetic resonance or threedimensional echocardiography, which may have introduced
errors in the estimation of LV volume/mass ratio, especially in
HCM patients. PCWP and t0 were estimated by non-invasive
means, which increased uncertainty in the estimation of the magnitude of the effect of relaxation on diastolic parameters. To overcome this, we studied a large patient population. The assessment
of t0 by our method has been tested in a variety of patient populations, but not specifically in HCM. However, basic mathematical
principles should be universal to all patients. Ample evidences corroborate preload sensitivity of E-wave, especially when controlled
for relaxation.6,10 As our regression model always included relaxation, we believe that E-wave velocity well reflected the impact
of preload. The most sensitive part of our t0 estimation is the calculation of PCWP estimate. Although several studies indicated that
E ‘corrected’ by Ea or Vp is robust enough to detect changes in
PCWP at a group level, this relationship seems poorer in the
setting of LV hypertrophy.40 However, our clinical data show the
precision is satisfactory for making accurate t0 estimation. It is
uncertain whether our findings can be generalized to other
patient populations, such as restrictive cardiomyopathy. Infiltrative
processes that occur in amyloidosis or Fabry’s disease affect both
wall thickness and structure, thus dramatically changing passive biomechanical characteristics of muscle tissue. Our aim was to assess
whether a change of relative thickness of LV wall with preserved
myocardial tissue characteristics affects diastolic function parameters. Additionally, HCM patients with LV outflow obstruction
frequently display septal bulge or sigmoid shape of the septum
that may have more impact on LV inflow than predicted from
measuring of LV volume/mass ratio. In our series of HCM patients,
exclusion of patients with significant LVOT gradient did not dramatically change the results.
Conclusions
LV volume/mass ratio correlated with flow propagation velocity,
early diastolic IVPGs, and UntwR even after adjusting for preload
and relaxation. This indicates that these diastolic function parameters have a previously unrecognized source of variability that
is independent of both intrinsic diastolic function (characterized
by t) and filling pressures. Because it is easy to calculate and clinically meaningful, LV volume/mass ratio should be considered when
assessing patients suspected of LV diastolic dysfunction regardless
of LV systolic function.
Supplementary material
Supplementary material is available at European Heart Journal
Online.
A. Buakhamsri et al.
Funding
Dr A.B. was funded by Faculty of Medicine, Thammasat University,
Bangkok, Thailand. This manuscript was supported through grants by
National Institutes of Health grant AG17479-02, National Space Biomedical Research Institute through NASA NCC 9-58 (Houston, TX),
Department of Defense (Ft. Dietrick, Md, USAMRMC grant no.
02360007), National Institutes of Health, National Center for Research
Resources, General Clinical Research Center (grant MO1 RR-018390),
and National American Heart Association grant 0235172N.
Conflict of interest: none declared.
References
1. Xie GY, Berk MR, Smith MD, Gurley JC, DeMaria AN. Prognostic value of
Doppler transmitral flow patterns in patients with congestive heart failure. J Am
Coll Cardiol 1994;24:132 –139.
2. Richartz BM, Werner GS, Ferrari M, Figulla HR. Comparison of left ventricular
systolic and diastolic function in patients with idiopathic dilated cardiomyopathy
and mild heart failure vs. those with severe heart failure. Am J Cardiol 2002;90:
390 –394.
3. Hillis GS, Moller JE, Pellikka PA, Gersh BJ, Wright RS, Ommen SR, Reeder GS,
Oh JK. Noninvasive estimation of left ventricular filling pressure by E/e’ is a
powerful predictor of survival after acute myocardial infarction. J Am Coll
Cardiol 2004;43:360–367.
4. Rihal CS, Nishimura RA, Hatle LK, Bailey KR, Tajik AJ. Systolic and diastolic dysfunction in patients with clinical diagnosis of dilated cardiomyopathy: relation to
symptoms and prognosis. Circulation 1994;90:2772 –2779.
5. Persson H, Lonn E, Edner M, Baruch L, Lang CC, Morton JJ, Ostergren J,
McKelvie RS. Diastolic dysfunction in heart failure with preserved systolic function: need for objective evidence: results from the CHARM Echocardiographic
Substudy-CHARMES. J Am Coll Cardiol 2007;49:687 –694.
6. Nagueh SF, Lakkis NM, Middleton KJ, Spencer WH III, Zoghbi WA, Quinones MA.
Doppler estimation of left ventricular filling pressures in patients with hypertrophic cardiomyopathy. Circulation 1999;99:254 –261.
7. Garcia MJ, Ares MA, Asher C, Rodriguez L, Vandervoort P, Thomas JD. An index
of early left ventricular filling that combined with pulsed Doppler peak E velocity
may estimate capillary wedge pressure. J Am Coll Cardiol 1997;29:448 –454.
8. Ommen SR, Nishimura RA, Appleton CP, Miller FA, Oh JK, Redfield MM, Tajik AJ.
Clinical utility of Doppler echocardiography and tissue Doppler imaging in the
estimation of left ventricular filling pressures: a comparative simultaneous
Doppler-catheterization study. Circulation 2000;102:1788 –1794.
9. Scalia GM, Greenberg NL, McCarthy PM, Thomas JD, Vandervoort PM. Noninvasive assessment of the ventricular relaxation time constant (t) in humans by
Doppler echocardiography. Circulation 1997;95:151–155.
10. Garcia MJ, Smedira NG, Greenberg NL, Main M, Firstenberg MS, Odabashian J,
Thomas JD. Color M-mode Doppler flow propagation velocity is a preload insensitive index of left ventricular relaxation: animal and human validation. J Am Coll
Cardiol 2000;35:201–208.
11. Thomas JD, Popovic ZB. Assessment of left ventricular function by cardiac ultrasound. J Am Coll Cardiol 2006;48:2012 –2025.
12. Baccani B, Domenichini F, Pedrizzetti G, Tonti G. Fluid dynamics of the left ventricular filling in dilated cardiomyopathy. J Biomech 2002;35:665 –671.
13. Schiller NB, Shah PM, Crawford M, DeMaria AN, Devereaux R, Feigenbaum H,
Gutgesell H, Reichek N, Sahn D, Schnittger I, Silverman NH, Tajik J. Recommendations for quantitation of the left ventricle by two-dimensional echocardiography. American Society of Echocardiography Committee on Standards,
Subcommittee on Quantitation of Two-Dimensional Echocardiograms. J Am Soc
Echocardiogr 1989;2:358 –367.
14. Corin WJ, Sutsch G, Murakami T, Krogmann ON, Turina M, Hess OM. Left ventricular function in chronic mitral regurgitation: preoperative and postoperative
comparison. J Am Coll Cardiol 1995;25:113 –121.
15. Greenberg NL, Vandervoort PM, Firstenberg MS, Garcia MJ, Thomas JD. Estimation of diastolic intraventricular pressure gradients by Doppler M-mode echocardiography. Am J Physiol Heart Circ Physiol 2001;280:H2507 –H2515.
16. Notomi Y, Lysyansky P, Setser RM, Shiota T, Popovic ZB, Martin-Miklovic MG,
Weaver JA, Oryszak SJ, Greenberg NL, White RD, Thomas JD. Measurement
of ventricular torsion by two-dimensional ultrasound speckle tracking imaging.
J Am Coll Cardiol 2005;45:2034 –2041.
17. Thomas JD, Flachskampf FA, Chen C, Guererro JL, Picard MH, Levine RA,
Weyman AE. Isovolumic relaxation time varies predictably with its time constant
Impact of LV volume/mass ratio on diastolic function
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
and aortic and left atrial pressures: implications for the noninvasive evaluation of
ventricular relaxation. Am Heart J 1992;124:1305 – 1313.
Popovic ZB, Prasad A, Garcia MJ, Arbab-Zadeh A, Borowski A, Dijk E,
Greenberg NL, Levine BD, Thomas JD. Relationship among diastolic intraventricular pressure gradients, relaxation, and preload: impact of age and fitness. Am J
Physiol Heart Circ Physiol 2006;290:H1454 –H1459.
Firstenberg MS, Levine BD, Garcia MJ, Greenberg NL, Cardon L, Morehead AJ,
Zuckerman J, Thomas JD. Relationship of echocardiographic indices to pulmonary
capillary wedge pressures in healthy volunteers. J Am Coll Cardiol 2000;36:
1664– 1669.
Popovic ZB, Sun JP, Yamada H, Drinko J, Mauer K, Greenberg NL, Cheng Y,
Moravec CS, Penn MS, Mazgalev TN, Thomas JD. Differences in left ventricular
long-axis function from mice to humans follow allometric scaling to ventricular
size. J Physiol 2005;568:255 –265.
Bland JM, Altman DG. Statistical methods for assessing agreement between two
methods of clinical measurement. Lancet 1986;1:307 –310.
Thomas JD, Zhou J, Greenberg N, Bibawy G, McCarthy PM, Vandervoort PM.
Physical and physiological determinants of pulmonary venous flow: numerical
analysis. Am J Physiol 1997;272:H2453 –H2465.
Thomas JD, Newell JB, Choong CY, Weyman AE. Physical and physiological
determinants of transmitral velocity: numerical analysis. Am J Physiol 1991;260:
H1718 –H1731.
Choong CY, Abascal VM, Thomas JD, Guerrero JL, McGlew S, Weyman AE.
Combined influence of ventricular loading and relaxation on the transmitral
flow velocity profile in dogs measured by Doppler echocardiography. Circulation
1988;78:672 –683.
Nagueh SF, Sun H, Kopelen HA, Middleton KJ, Khoury DS. Hemodynamic determinants of the mitral annulus diastolic velocities by tissue Doppler. J Am Coll
Cardiol 2001;37:278 – 285.
Prasad A, Popovic ZB, Arbab-Zadeh A, Fu Q, Palmer D, Dijk E, Greenberg NL,
Garcia MJ, Thomas JD, Levine BD. The effects of aging and physical activity on
Doppler measures of diastolic function. Am J Cardiol 2007;99:1629 –1636.
Jacques DC, Pinsky MR, Severyn D, Gorcsan J III. Influence of alterations in loading
on mitral annular velocity by tissue Doppler echocardiography and its associated
ability to predict filling pressures. Chest 2004;126:1910 – 1918.
Firstenberg MS, Greenberg NL, Main ML, Drinko JK, Odabashian JA, Thomas JD,
Garcia MJ. Determinants of diastolic myocardial tissue Doppler velocities: influences of relaxation and preload. J Appl Physiol 2001;90:299 – 307.
Dong SJ, Hees PS, Huang WM, Buffer SA Jr, Weiss JL, Shapiro EP. Independent
effects of preload, afterload, and contractility on left ventricular torsion. Am J
Physiol 1999;277:H1053 –H1060.
1221
30. Cheng Y, Oertel H, Schenkel T. Fluid-structure coupled CFD simulation of the left
ventricular flow during filling phase. Ann Biomed Eng 2005;33:567 –576.
31. Ingels NB Jr, Hansen DE, Daughters GT II, Stinson EB, Alderman EL, Miller DC.
Relation between longitudinal, circumferential, and oblique shortening and torsional deformation in the left ventricle of the transplanted human heart. Circ
Res 1989;64:915 – 927.
32. Nagel E, Stuber M, Burkhard B, Fischer SE, Scheidegger MB, Boesiger P, Hess OM.
Cardiac rotation and relaxation in patients with aortic valve stenosis. Eur Heart J
2000;21:582 –589.
33. Notomi Y, Martin-Miklovic MG, Oryszak SJ, Shiota T, Deserranno D, Popovic ZB,
Garcia MJ, Greenberg NL, Thomas JD. Enhanced ventricular untwisting during
exercise: a mechanistic manifestation of elastic recoil described by Doppler
tissue imaging. Circulation 2006;113:2524 – 2533.
34. Unverferth DV, Magorien RD, Moeschberger ML, Baker PB, Fetters JK, Leier CV.
Factors influencing the one-year mortality of dilated cardiomyopathy. Am J Cardiol
1984;54:147 –152.
35. Yu CM, Zhang Q, Yip GW, Lee PW, Kum LC, Lam YY, Fung JW. Diastolic and
systolic asynchrony in patients with diastolic heart failure: a common but
ignored condition. J Am Coll Cardiol 2007;49:97 –105.
36. Wang M, Yip GW, Wang AY, Zhang Y, Ho PY, Tse MK, Lam PK, Sanderson JE.
Peak early diastolic mitral annulus velocity by tissue Doppler imaging adds independent and incremental prognostic value. J Am Coll Cardiol 2003;41:820–826.
37. Nikitin NP, Loh PH, Silva R, Ghosh J, Khaleva OY, Goode K, Rigby AS, Alamgir F,
Clark AL, Cleland JG. Prognostic value of systolic mitral annular velocity
measured with Doppler tissue imaging in patients with chronic heart failure
caused by left ventricular systolic dysfunction. Heart 2006;92:775 –779.
38. Troughton RW, Prior DL, Frampton CM, Nash PJ, Pereira JJ, Martin M, Fogarty A,
Morehead AJ, Starling RC, Young JB, Thomas JD, Lauer MS, Klein AL. Usefulness
of tissue doppler and color M-mode indexes of left ventricular diastolic function
in predicting outcomes in systolic left ventricular heart failure (from the ADEPT
study). Am J Cardiol 2005;96:257 –262.
39. Liang HY, Cauduro SA, Pellikka PA, Bailey KR, Grossardt BR, Yang EH, Rihal C,
Seward JB, Miller FA, Abraham TP. Comparison of usefulness of echocardiographic Doppler variables to left ventricular end-diastolic pressure in predicting
future heart failure events. Am J Cardiol 2006;97:866 –871.
40. Geske JB, Sorajja P, Nishimura RA, Ommen SR. Evaluation of left ventricular filling
pressures by Doppler echocardiography in patients with hypertrophic cardiomyopathy: correlation with direct left atrial pressure measurement at cardiac
catheterization. Circulation 2007;116:2702 – 2708.