Ultrasound in Med. & Biol., Vol. 28, Nos. 11/12, pp. 1395–1403, 2002
Copyright © 2002 World Federation for Ultrasound in Medicine & Biology
Printed in the USA. All rights reserved
0301-5629/02/$–see front matter

PII: S0301-5629(02)00644-0● Original Contribution
LEFT VENTRICULAR TRANSMURAL SYSTOLIC FUNCTION BY HIGHSENSITIVITY VELOCITY MEASUREMENT “PHASED-TRACKINGMETHOD” ACROSS THE SEPTUM IN DOXORUBICIN
CARDIOMYOPATHY
YOSHIRO KOIWA,* HIROSHI KANAI,‡ HIDEYUKI HASEGAWA,‡ YOSHIKO SAITOH† and
KUNIO SHIRATO*
Departments of *Cardiovascular Medicine and †Immunology and Hematology Medicine, Tohoku University
Graduate School of Medicine, Aoba-ku, Sendai, Japan; and ‡Department of Electronic Engineering, Graduate Schoolof Engineering, Tohoku University, Sendai, Japan(Received 2 January 2002; in final form 6 August 2002)

Abstract—The clinical usefulness of doxorubicin is limited by doxorubicin-induced cardiomyopathy (DoxCM).
The prognosis of this disorder is poor, and a sensitive noninvasive method for detection of DoxCM is strongly
required. In this study, we examined if the transmural systolic function (TSF) obtained by the novel phasedtracking method is capable of supplying new information on DoxCM. A total of 18 healthy subjects and 30
patients with acute lymphoblastic leukemia were examined for TSF, as defined by the transmural profile of %thickening obtained by measuring the velocity at each preset point of 0.75-mm intervals. The total number ofmeasurements was 94. In the patients, a decrease in both the peak velocity and the systolic layer thickening wasobserved, even in the subclinical phase of the normal ejection fraction. For healthy subjects, systolic thickening
occurred in the left ventricular (LV) side of the interventricular septum (IVS), and was characterized by a sharp
single-peak configuration of the profile. For the patients, however, the peak became dull and/or unclear, whichindicates that a change in transmural functional distribution occurred. We concluded that the TSF is a usefulmeasure for diagnosis of the early phase of DoxCM. (E-mail: koiwa@intl.med.tohoku.ac.jp) © 2002 World
Federation for Ultrasound in Medicine & Biology.
Key Words: Doppler measurement, Intramyocardial velocity, Myocardial layer thickening, Transmural systolic
function, Doxorubicin cardiomyopathy.

intraventricular septum (IVS) are not as sensitive for
DoxCM as specimens from the LV side of the IVS. This
indicates that we should perform left heart catheterization, although this is usually considered as being beyond
the bounds of daily clinical practice (Mortensen et al.
1986). A recent approach to protection against DoxCM
by the parallel use of antioxidants shows some therapeutic promise (Morishima et al. 1998; Siveski-Iliskovic etal. 1995). This possibility of eliminating the cardiotoxic
effects further highlights the need to develop noninvasive methods for long-term repetitive monitoring, notwithstanding the many approaches, such as exercise
echocardiography, radionuclide angiography and the
Doppler technique (Choi et al. 1988; Marchandise et al.
1989; Palmeri et al. 1986; Weesner et al. 1991). Practically, as detailed in several reviews (Doroshow 1991;
Dunn 1994), no adequate diagnostic method for estimating subclinical myocardial damage in daily clinical prac-

INTRODUCTION
Doxorubicin (adriamycin) is an antineoplastic agent effective against a wide range of solid or hematologic
malignancies. Its use is, however, often limited by cardiomyopathy (DoxCM) (Lipshultz et al. 1991; Steinherz
et al. 1991). As for the diagnosis of DoxCM, endomyocardial biopsy has been considered as the “gold standard” for evaluating the magnitude of the induced damage. This invasive technique, however, can hardly be
used in cases of heart failure or for long-term follow-up,
and the results may be contaminated by biopsy error(Dunn 1994). Moreover, it has been reported that biopsy
specimens from the right ventricular (RV) side of the

Address correspondence to: Prof. Yoshiro Koiwa, Department of
Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Seiryou-machi 1-1, Aoba-ku, Sendai 980-8574, Japan. E-mail:koiwa@int1.med.tohoku.ac.jp
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Table 1. Experimental-results on the transmural systolic thickening
Reference

Materials
preparation

Contribution to the total wall
thickening (mean ⫾ SD)

Gallagher et al. 1985

conscious dog

Myers et al. 1986

open chest dog

Sabbah et al. 1981

open chest dog

Myers et al. 1984

dog heart

Bolli et al. 1984

conscious dog

inner 1/2 ⫽ total-outer: 71 ⫾ 9%outer 1/2: 29.9 ⫾ 9%
inner 1/3: 58%
middle 1/3: 25%
outer 1/3: 17%
endocardium (theoretical) 1/2:83%
epicardium (theoretical) 1/2:17%
inner 1/2: 71%
outer 1/2: 29%
inner 1/3: 46 ⫾ 4%
middle 1/3: 27 ⫾ 2%outer 1/3: 19 ⫾ 2%

In experimental studies, the number of layers was limited to two or three. The myocardium on the LV side (inner, endocardium or
inner ⫹ middle in reports) showed greater thickening during systole, which corresponds to the existence of functional heterogeneity(physiological heterogeneity) across the wall. The term “theoretical” in (3) means estimation from theoretical drawing.

tice has yet been established, despite the fact that avariety of parameters have been proposed. Lipshultz etal. (1991) stressed that increased LV afterload (measured
as end-systolic wall stress) due to the reduction in wall
thickness was a key factor for determining the clinicalcourse of 115 children at 1 to 15 years from the end oftreatment. Their conclusion that the increase in afterload
might have occurred primarily due to impaired myocardial growth by doxorubicin injection is a persuasive
example of the pathophysiology of this DoxCM.
It has been confirmed, mainly in experimental models, that transmural systolic functional heterogeneity exists in the normal heart (physiologic heterogeneity) because the dominant layer of thickening lies in the heart
wall on the LV side (Gallagher et al. 1985; Myers et al.
1986; Sabbah et al. 1981). Table 1 summarizes theheterogeneous TSF in previously reported experiments.
The observed change of magnetic resonance image(MRI) tagging in the endocardium, myocardium andepicardium with regard to this physiologic functional
heterogeneity in hypertrophic cardiomyopathy or myocardial infarction has been considered as being important
in interpretation of the pathophysiology of the disease(Bogaert et al. 1999; Dong et al. 1994). For patients
under doxorubicin treatment, however, an approach tomonitoring of the myocardial damage from the viewpoint of transmural heterogeneous behavior has neverbeen examined. This is despite the fact that the morphological damage, including fibrous thickening, has been
more pronounced in the LV side of the IVS in patients(Mortensen et al. 1986). This suggests that the histological change in the myocardium occurs heterogeneously
across the wall and generates further complexity in thepathophysiology of this disease.
At present, three diagnostic methods (tissue Doppler
imaging or TDI, integrated backscatter, and magnetic

resonance imaging or MRI tagging) are considered to bepotentially useful for evaluating transmural functional
heterogeneity (Colonna et al. 1999). However, several
problems remain to be solved. For example, for myocardial slow motion and change in wall thickness, MRI
tagging is limited to several mm in the spatial resolution
and several tens of ms in the time resolution (Bogaert etal. 1999; Dong et al. 1994; Maier et al. 1992). Conventional 2-D color flow mapping instruments have been
modified to acquire low-frequency large-amplitude
Doppler signals in TDI, and slow tissue motions toward
the transducer and away from the transducer are, respectively, color-coded in red and blue on the B-mode or
M-mode echocardiographic image (Donovan et al. 1995;
Gorcsan et al. 1997).
Kanai et al. (1996) have reported a novel ultrasonicbased method to accurately track the large motion of apoint preset in the myocardium, based on both the phaseand magnitude of the signal reflected at the point. By thismethod, velocity signals of small amplitude, v(t; xi), of apoint i at a depth of xi in the ventricular wall, which areless than several ␮m and up to about 100 Hz on the large
motion resulting from a heartbeat, can be detected with
sufficient reproducibility. By integrating the difference inthe resulting velocity signals at two preset points along
the ultrasonic beam, a minute change in thickness ofseveral tens of ␮m has been detected with high temporaland spatial resolution (Kanai et al. 1997). The ␮m-order
velocity of the myocardial thickening can be separated
from the large wall motion by this method. In patientswith aortic valve stenosis, for example, the transmissionof vibration across the septum has been demonstrated bythis method (Kanai and Koiwa 2001). That is, the systolic ejection murmur at the aortic root was transmitted
heterogeneously and regionally to the intramyocardial

Transmural function in DoxCM ● Y. KOIWA et al.

preset points in the basal region of the LV side of the
septum.
From histological examinations using doxorubicininjected rabbits, the TSF has been confirmed to beclosely related to the magnitude of myocardial damage(Koiwa et al. 1998). One of the advantages of thismethod is that it yields information on the patient’s
transmural functional heterogeneity of the ventricularwall with extremely high resolution compared with previous methods. Thus, we aimed to clarify if this novel
Doppler method, the phased-tracking method, can be ofuse for diagnosis in patients with DoxCM.
METHODS
Subjects
We examined the following subjects from April
1995 to March 1999: 18 healthy subjects (25.7 ⫾ 7.9
years old; male) and 30 patients with acute lymphoblastic leukemia (32.9 ⫾ 11.8 years old; 17 male and 13
female) who were receiving mitoxantrone hydrochloride(HCl) injection as a part of their combined chemotherapy
treatment. Among these subjects, 4 healthy volunteers
and 9 patients were examined repeatedly during thestudy period, the total number of measurements being 94(24 times for healthy subjects and 70 times for patients).
During this period, 5 patients; 2 died from relapse of themalignancy and 3 died from DoxCM. Except during theterminal stage of these patients, measurements were carried out at an outpatient clinic. The dose of mitoxantrone
HCl was converted to an equivalent dose of doxorubicin.
The value of the administered dose normalized by bodysurface area (Dose/BSA) was 480.9 ⫾ 89.0 mg/m2.
Measurement of conventional LV function in the routine
echocardiographic method
Using ultrasonic diagnostic equipment (Toshiba,
SSH 160A, Tokyo, Japan), the following seven parameters were measured by a conventional echo Doppler
method during the follow-up period: 1. LV end-diastolic
diameter (LVDd); 2. LV end-systolic diameter (LVDs);
3. wall thickness of the interventricular septum (IVSWT)at end-diastole; 4. ejection fraction (EF); 5. peak velocityof E-wave (E); 6. peak velocity of A-wave (A) and 7.
E:A ratio.
Measurement of myocardial layer thickening
By taking into consideration the results of an MRI
tagging study that showed that the septum of the ventricle exhibited far less 3-D movement during the cardiac
contraction compared with other regions of the anteriorwall, posterior wall, and apex (Maier et al. 1992), TSF
was obtained at the basal anteroseptal segment of the
IVS, where the ultrasonic beam was projected at an angle

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almost normal to the IVS. That is, the direction of theultrasonic beam passing through the measurement points
was selected in the longitudinal, B-mode cross-sectional
image so as to be almost perpendicular to the IVS during
the measurements. Just after the selection, the directionof the ultrasonic beam was fixed and the quadraturedemodulated signal of the RF signal was A/D converted
during several heartbeats. By selecting the ultrasonicbeam passing through the measured points so that it isperpendicular to the heart wall in the cross-sectional
images along the conventional longitudinal axis, it has
been experimentally confirmed that the measured point isalmost perpendicular to the heart wall during the measurements (Kanai et al. 1996).
The principle of the phased-tracking method, including the theoretical and in vivo evaluations for the
myocardial layer thickening rate, has been detailed previously (Kanai et al. 1996, 1997). In brief, radiofrequency (RF) pulses with an angular frequency of ␻0 ⫽2␲f0 are transmitted at time intervals of ⌬T from anultrasonic transducer on the chest wall. The phase difference, ⌬␪(x;t), between the phase ␪(x;t) of the quadrature-demodulated signal of the received signal, y(x;t),
and the phase ␪(x;t ⫹ ⌬T) of the quadrature-demodulated signal of the subsequently received signal, y(x;t ⫹⌬T), is given by:⌬ ␪ 共 x;t兲 ⫽ ␪ 共 x;t ⫹ ⌬T兲 ⫺ ␪ 共 x;t兲 ⫽2␻0⌬x共t兲,
c0(1)

where ⌬x(t) ⫽ x(t ⫹ ⌬T) ⫺ x(t) is the movement of theobject during the period ⌬T around time t, and c0 is theacoustic velocity in the human body. In our examination,
the period ⌬T was set at 250 ␮s. Because the maximum
value of the acceleration in the IVS is about 4 m/s2
(Kanai et al. 1996), the velocity of the IVS changes by
0.001 m/s at most, which is 1/400 of the higher limit of
the measurable velocity (0.4 m/s), for the short period ⌬Tof 250 ␮s. Thus, the velocity of the IVS is assumed to beconstant during the pulse-repetition interval ⌬T. By dividing the movement ⌬x by the period ⌬T, the averagevelocity v(t ⫹ ⌬T/2) of the object during the period ⌬T
is given by:

冉

␯ t⫹

冊

⌬T
⌬x共t兲
c 0 ⌬ ␪ 共 x;t兲
⫽
·
⫽
.
2
⌬T
2␻0
⌬T

(2)

The phase difference ⌬␪(x;t) is accurately determined by the constraint least squares approach based on
the complex cross-correlation between y(x;t) and y(x;t ⫹⌬T), under the condition that the signal waveforms do
not change except that their phase values change during
the period ⌬T. It is impossible to accurately determine

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the true lag value from the complex correlation function,
which is derived from the standard normalized meansquared difference between the quadrature-modulated
signals of the successively received signals (Kanai et al.
1996). However, the introduction of the constraint iseffective for the determination of the lag between thesecomplex signals. By multiplying the resultant velocity (t⫹ ⌬T/2) by the period ⌬T, the next depth x(t ⫹ ⌬T) of
the object is estimated by:冉

x共t ⫹ ⌬T兲 ⫽ x共t兲 ⫹ ␯ˆ t ⫹

冊

⌬T
⫻ ⌬T,
2

(3)

Using the resultant signal x(t ⫹ ⌬T), the displacement of
the object (the position of the region of interest or ROI)in the heart wall is successfully tracked, and then thevelocity signal ␯|Ax(t) on the large motion due to theheartbeat is accurately measured.
In practice, a high-speed A/D converter with alarge-scale memory was employed to analyze the complex signal resulting from the quadrature modulation of
the signal received by a sector-type ultrasonic transducer
connected to standard ultrasonic diagnostic equipment.
The employed ultrasonic frequency, f0, was 3.75 MHz,and the repetition interval ⌬T of the pulses was 222 ␮s.
The resultant real and imaginary signals of the demodulated Doppler signal were simultaneously A/D converted with a 2-channel 12-bit A/D converter at a sampling rate of 1 MHz. The initial positions of the multiple
sampling points across the wall were manually set al.ong
the ultrasonic beam at the timing of the peak R in theelectrocardiogram (ECG). The lower limit of the resolution of the change in layer thickness was 0.5 ␮m, and thehigher limit of the measurable velocity was about 0.4
m/s, which was determined by aliasing with the conventional Doppler system (Kanai et al. 1997).
Measurement of TSF
By defining the systole as the period between theonset of the Q wave in ECG and the second heart sound,the following seven parameters of TSF were measured:
1. maximum velocity (peakV) and 2. maximum negative
velocity (negV) of the transmural preset points; 3. theprofile of the percent of thickening, defined by the systolic thickness divided by the thickness at the timing of
the R wave, at each layer across the IVS (% thickening);
4. maximum percent of thickening of the layer across thewall at systole (max%Tkn); 5. the number of functioning
layers showing thickening greater than 110% at systole(#Nf); 6. percent of the number of functioning layers
across the wall (%Nf); and 7. percent of the nonfunctioning layers at systole (%Nn).

Volume 28, Numbers 11/12, 2002

Reproducibility of parameters of TSF
To evaluate the observational variability of the measurement of TSF, two independent observers measured
the parameters of TSF at intervals of approximately 5
min for 22 subjects (9 healthy and 13 patients) to evaluate the interobserver variability. The repeatability of
TSF was assessed in 19 subjects (8 healthy and 11
patients) by two sequential measurements approximately
30 min apart.
Statistics
All values are expressed as mean ⫾ SD, unlessotherwise indicated. Analysis of variance (ANOVA) wasused to assess the difference in each variable between
healthy subjects and patients. When statistically significant results were found, post hoc individual comparison
was made with Bonferroni’s test. Simple regression analysis was used to determine if it was possible to estimate
the magnitude of each variable from the routine ECG
method and TSF or Dose/BSA. A two-tailed p value ofless than 0.05 was considered to indicate statistical significance. Multiple stepwise regression with the forwardincrement method was used to examine the links between the max%Tkn, peakV, negV or %Nf and variablesof age, body length, body weight, systolic blood pressure, diastolic blood pressure, heart rate (HR), LVDd,
LVDs, IVSWT, EF, and Dose/BSA (F-to-enter value ⬎4.00).
RESULTS
There was good agreement in the interobserver variability for TSF, namely, the SD accounted for 7%, 10%,8%, 8% and 11% of the measured max%Tkn, peakV,
negV, %Nf and %Nn, respectively. The repeatability was
18%, 15%, 19%, 12% and 20% in SD, respectively, foreach of the above parameters. No significant differencein each parameter was observed between the first andsecond measurements, nor between operators.
Table 2 shows the baseline characteristics in healthy
subjects and patients. Figure 1a shows an image of the
TSF at the septum for a healthy subject (a 22-year-oldman) and Fig. 1b shows that for a patient (a 25-year-oldman) undergoing treatment with a mild dose of doxorubicin (360 mg/m2 of BSA), where EF ⫽ 64%. From top
to bottom, Fig. 1 shows the M-mode image of the echocardiography, ECG, superposition of the velocity signals
at all preset points (13 points in Fig. 1a and 15 points in
Fig. 1b), and the change in thickness of each layer where
the RV surface is flat. In the superposition of the velocity
signals from each preset point within the myocardial
layers, the difference in velocities corresponds to thechange in thickness of the layer; they were much more
remarkable for the healthy subject than for the patient at

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Table 2. Clinical features and baseline characteristics inpatients with doxorubicin injection and healthy subjects

Age (y)Body length (cm)Body weight (kg)
BSA (m2)
Systolic BP (mmHg)
Diastolic BP (mmHg)
HR (1/min)(1) LVDd (mm)(2) LVDs (mm)(3) IVSWT (mm)(4) EF (%)(5) E (m/s)(6) EA

Patients

Healthy subjects

p value

32.8 ⫾ 11.2
161.4 ⫾ 6.5
58.8 ⫾ 9.0
1.6 ⫾ 0.1
118.7 ⫾ 15.8
78.0 ⫾ 11.7
81.1 ⫾ 16.1
48.5 ⫾ 5.3
32.1 ⫾ 7.1
8.3 ⫾ 1.8
57 ⫾ 1
0.6 ⫾ 0.2
1.3 ⫾ 0.5

25.7 ⫾ 7.9
170.9 ⫾ 5.4
65.0 ⫾ 6.7
1.8 ⫾ 0.1
123.9 ⫾ 8.5
72.7 ⫾ 7.5
68.6 ⫾ 8.8
48.3 ⫾ 3.4
30.0 ⫾ 3.9
8.9 ⫾ 1.2
65 ⫾ 80.8 ⫾ 0.2
1.6 ⫾ 0.3

†
‡
†
†

*
*
‡

*
*
†

*
†

Each value is expressed as mean ⫾ SD. The meanings of terms(1)–(6) are described in the beginning of Methods section. *p ⬍ 0.05,†
p ⬍ 0.01; ‡p ⬍ 0.001.

systole. As for the magnitude of the systolic thickening at
each layer, as shown at the bottom of Fig. 1a, there wasa difference across the wall, especially in the healthy
subject; namely, the magnitude was larger at the middle
to LV side of the septum during early and late systole.
That is, there was physiological heterogeneity across thewall (physiological heterogeneity) in the healthy subject.
For the patient, however, as shown at the bottom of Fig.
1b, the peak thickening and thickening rate were muchsmaller than those of the healthy subject.
The transmural systolic thickening (%) in each thirdof the septum from the RV side to the LV side was 27.6
⫾ 2.6%, 31.8 ⫾ 2.4%, and 40.4 ⫾ 3.0%, respectively, in
healthy subjects. Figure 2 shows a profile of the heterogeneous thickening across the wall for healthy subjects.
The maximum of the percent of thickening of thelayer across the wall at systole, max%Tkn, in the healthy
subjects was 223 ⫾ 46%, that is, from 300% to 180%,
and no thinning was observed. The parameters on transmural functional heterogeneity derived from the TSF
showed significant differences between healthy subjects
and patients as summarized in Table 3. Maximum velocity (peakV), maximum negative velocity (negV) at thepreset point, and max%Tkn were larger in healthy subjects. For patients, on the other hand, the percent of thenumber of functioning layers across the wall, %Nf, wassmaller and the percent of the nonfunctioning layers at
systole, %Nn, was larger.
Figure 3 shows the relationships between the ejection fraction (EF) and the four parameters (%Nf,
max%Tkn, negV, and peakV) in the TSF. The lower
limit of the normal range of EF (mean-SD value in our
university hospital) and the mean-SD values of TSF fromhealthy subjects in this report are expressed by a solidline. These relationships are summarized as follows:

Fig. 1. The thickening of each myocardial layer during the
cardiac cycle. (a) A healthy 22-year-old man; (b) a 25-year-old
man under doxorubicin treatment. From top to bottom in eachfigure, M-mode echocardiography, ECG, superposition of velocity signals at each preset point at different depths (0.75 mm
interval; the first point was set at the right ventricular endocardial surface), the changes in thickness of the transmural layers
during the cardiac cycle, where the RV surface of the septum
was set as no movement to facilitate understanding of thedifferences among layers. The vertical dotted line indicates
R-wave timing of ECG. The arrow shows the timing of the
maximum velocity during systole.

peakV (m/s) ⫽ 0.005 ⫹ 0.151 ⫻ EF(%),
r ⫽ 0.38, p ⬍ 0.01
negV (m/s) ⫽ 0.006 ⫹ 0.001 ⫻ EF(%),
r ⫽ 0.32, p ⬍ 0.01
max%Tkn (%) ⫽ 73.9 ⫹ 1.79 ⫻ EF(%),
r ⫽ 0.62, p ⬍ 0.01

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Fig. 2. Profiles of max%Tkn across the septum in healthy
subjects. The magnitude of thickening is different among layers
across the wall and the layer of maximum thickening extends
from the middle wall to LV side. The maximum systolic
thickening showed values approximately 200% larger.

%Nf (%) ⫽ 23.2 ⫹ 0.65 ⫻ EF(%),
r ⫽ 0.31, p ⬍ 0.01.
There were significant relationships between EF and
TSF, and even the r value was not so strong. As plottedin the right lower quadrant in each part of Fig. 3, many
patients maintained a normal EF despite the fact that the
TSF was reduced compared to the normal range (horizontal solid line). This indicates that the deterioration of
the TSF precedes the conventional global ventricularfunction in many cases.

Table 3. Seven parameters of TSF derived from the velocity
measurement at intramural preset/points in patients withdoxorubicin injection and healthy subjects

1. max % Tkn
2. peakV (m/s)
3. negV (m/s)
4. #Nf
5. %Nf (%)
6. #Nn
7. %Nn (%)

Patients

Healthy subjects

p value

169 ⫾ 34
0.024 ⫾ 0.010
0.037 ⫾ 0.014
6.60 ⫾ 2.10
57.6 ⫾ 19.3
3.4 ⫾ 1.9
28.2 ⫾ 14.1

223 ⫾ 46
0.034 ⫾ 0.007
0.048 ⫾ 0.014
8.88 ⫾ 2.31
76.9 ⫾ 11.6
2.5 ⫾ 1.7
20.5 ⫾ 11.8

‡
‡
†
‡
‡

*
*

1. max%Tnk ⫽ maximum thickening rate of the myocardial layer
across the septum; 2. peakV ⫽ peak velocity during contraction phaseat a preset point in the myocardial wall; 3. negV ⫽ peak negative
velocity during relaxation phase at a preset point; 4. #Nf ⫽ the numberof functioning layers showing thickening at systole at the midtiming of
the first and second heart sounds; 6. #Nn ⫽ the number of nonfunctioning layers; 5. %Nf and 7. %Nn ⫽ the percentage of each parameter(#Nf, #Nn) through the septum; p value ⫽ *p ⬍ 0.05; †p ⬍ 0.01; ‡p ⬍0.001.

Fig. 3. The relationships between EF and the four parameters(%Nf, max%Tkn, negV, and peakV) of the TSF for the patientswith DoxCM (●) and healthy subjects (E). There is a significant relationship between TSF and EF. Solid lines indicate thelower limit of the normal range (mean-SD value). Many patients demonstrated a decrease in the TSF values but still
showed normal EF values.

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From multiple stepwise regression analysis using all
variables listed in the tables, EF, E and negV were shownto correlate significantly with the magnitude of peakV.
Also, EF and peakV were selected for negV, and variables of age, HR, LVDd, peakV and #Nf were selected
for max%Tkn. However, no terms from the global function were selected for %Nf (wall thickness andmax%Tkn were selected variables, but R2 was only
0.22).
The relationship is summarized as follows
PeakV ⫻ 250 (m/s) ⫽ (⫺5.13 ) ⫻ (EF ⫻ 100%) ⫹ 3.69
⫻ E ⫹ 0.42 ⫻ negV ⫻ 250 (m/s) ⫹ 2.53, p ⬍ 0.0001,
R2 ⫽ 0.549, F-to-remove value from first to third
variables; 4.544, 11.967, 47.364
negV ⫻ 250 (m/s) ⫽ 7.799 ⫻ (EF ⫻ 100%) ⫹ 1.057 ⫻peakV ⫻ 250 (m/s) ⫹ (⫺1.346), p ⬍ 0.0001, R2 ⫽0.471, F-to-remove value for first and second variables: 4.029, 48.846.
max%Tkn/100 (%) ⫽ (⫺0.009) ⫻ age ⫹ (⫺0.006) ⫻HR ⫹ (⫺0.016) ⫻ LVDd (mm) ⫹ (0.056) ⫻ #Nf ⫹(0.041) ⫻ peakV ⫻ 250 (m/s) ⫹ 2.602, p ⬍ 0.0001,
R2 ⫽ 0.420, F-to-remove value from first to fifth
variables 6.317, 8.974, 5.815, 13.559, 7.852%Nf/100 (%) ⫽ (⫺0.03) ⫻ wall thickness ⫹ (0.264) ⫻max%Tkn ⫻ 1/100 (%) ⫹ 0.396, p ⬍ 0.001, R2 ⫽0./221, F⫽to-remove vaue for first and second variables: 5.644, 12.149

Fig. 4. Top: ECG and superposition of velocity signals at eachpreset point across the septum from 1995 to 1999 in a 23-yearold male patient, 1995, in stable condition of complete remission. Arrow indicates the peak velocity during systole. Bottom:
The change in the profile of max%Tkn at each layer across theseptum.

DISCUSSION
Clinical evaluation of myocardial functional deterioration under doxorubicin injection is an essential requirement in the management of patients with hematologic malignancy and a variety of cancers. In particular,
early detection at a subclinical phase of myocardial damage is significant because heart failure, after it becomesmanifest, irreversibly proceeds to a therapy-resistantstage of failure.
In this study using the phased-tracking method, theexistence of physiological transmyocardial heterogeneityin humans was demonstrated and a major part of thesystolic thickening was found to be caused by the contribution of the middle and left side of the ventricularwall. That is, the functional importance of the midmyocardial side to the endomyocardial side of the left ventricle during systole was consistent with experimental
reports, as summarized in Table 1. The temporal change
in this transmural function in healthy subjects duringsystole has been recently reported by our laboratory(Koiwa et al. 2002).

As shown in Fig. 3, the sequential change of parameters of the TSF in many patients differed from that of
the conventional parameters: many patients showed anabnormal TSF even though EF remained normal. Moreover, TSF seemed to be a good indicator of myocardialdamage during the clinical course. For example, in the
TSF from a patient (a 23-year-old man in 1995, 485
mg/m2 of BSA) in complete remission, as shown in Fig.
4a, b and c, the velocity during systole (arrow) showed agradual decrease from 1995 to 1999 and the profile inFig. 4d also indicates a gradual decrease in the
max%Tkn.
However, these changes over 4 years were relatively small in magnitude compared with the changes
over 5 months in another patient, who died of DoxCM
5 months after the first measurement, as shown in Fig.
5. Thinning, not thickening, occurred during systole inthis case of serious DoxCM. The rapidity of thechange was in sharp contrast to that of the patient instable condition, as demonstrated in Fig. 4. Parametersfrom conventional routine ECG did not sensitively

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Ultrasound in Medicine and Biology

Volume 28, Numbers 11/12, 2002

Fig. 5. Superposition of profiles of max%Tkn during 5 months
in a patient who died in September 1995 from congestive heart
failure. The rapid change in the profile and the appearance ofthe systolic thinning are in sharp contrast to those of healthy
subjects in Fig. 2 and those of the patient in stable condition in
Fig. 4.

reflect the change that potentially occurred in theventricular myocardium (e.g., EF remained within normal limits even 5 months before death in this patient).
The possibility of evaluating myocardial damage in aclinical setting using the phased-tracking method is also
demonstrated in Fig. 6 for three other patients who diedfrom DoxCM.
The TSFs showed increasing deterioration during
their courses, but EF showed fluctuations from normal
to abnormal values, probably due to the parameters’
preload and afterload dependency. The histologicalexamination of rabbit IVS has confirmed that the
myocardial layer function (max%Tkn) shows an inverse linear relationship to the magnitude of the myocardial damage (% of the pathologic lesion that was
fibrous and edematous in each area of the myocardial
layer) (Koiwa et al. 1998). We speculate that the layer
function in the human ventricular wall also reflects, atleast in part, the magnitude of the histological deterioration by DoxCM (Bristow et al. 1981), as demonstrated in the animal study.
As shown in Figs. 2 and 3b, when the max%Tkn
decreases to less than 200%, we should carefully monitor
the patient at an earlier phase of cardiac toxicity, evenwhen the value of EF still remains normal. In particular,
the decrease in %Nf or the appearance of transmuralsystolic thinning should be interpreted as indicative ofserious histological and functional deterioration in the
myocardium caused by doxorubicin injection. The %Nf
is an independent parameter of global function obtainedby routine measurement, and %Nf can be evaluated onlyby this highly sensitive velocity measurement method,that is, the phased-tracking method.

Fig. 6. The sequential change of the three parameters(max%Tkn, peakV, and %Nf, from top to bottom) in the TSF
and EF during the clinical course (from 1 to 3 or 4) in threepatients that died from DoxCM. In those patients, TSF indicated gradual deterioration during the course, but EF showedsignificant fluctuation from normal to abnormal.

CONCLUSION
Quantitative information on doxorubicin-induced
myocardial damage was obtained by assessing myocardial layer thickening using the phased-tracking method.
Information so obtained, therefore, is potentially usefulfor the rational management of patients with leukemia,
malignant lymphoma or other serious diseases requiring
treatment with doxorubicin.

Transmural function in DoxCM ● Y. KOIWA et al.
Acknowledgments—The authors are grateful to Prof. Emeritus Noriyoshi Chubachi and Prof. Emeritus Motonao Tanaka of Tohoku University, Floyd Dunn of the Bioacoustic Research Laboratory, the University of Illinois, Dr. Hide-ichi Kamada of Tohoku University School of
Medicine, and Dr. Hideyuki Honda of Tohoku Bunka Gakuen University for helpful discussion and instruction. The authors also acknowledge the contribution of Dr. Yoshiro Uzuka of the Sendai Blood
Disease Center for clinical support. This work was supported in part by
grants-in-aid for scientific research from the Ministry of Education,
Culture, Sports, Science and Technology of Japan (1993, 1994, 1996,
1997 to 1998, 1999 and 2000).

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