Download Dobutamine stress echocardiography: A sensitive indicator of

394

JACC Vol . N, No 2 February 1992'Iso-aui

Dobutamine Stress Echocardiography : A Sensitive Indicator of Diminished Myocardial Function in Asymptomatic DoxorubicinTreated Long-Term Survivors of Childhood Cancer SCOTT E . KLEWER, BS, STANLEY J . GOLDBERG, MD, FACC, RICHARD L . DONNERSTEIN, MD, FACC, ROBERT A . BERG, MD, JOHN J. HUTTER, JR ., MD Tucson, Arizona

Doxorubicin is an effective anticancer chemotherapeutle agent known to cause acute and chronic cardiomyepathy . To develop a more sensitive echocardiographic screening test for cardiac damage due to desarubicto, a cohort study was performed using dobutandne infusion to differentiate asymptomalk long-term survivors of childhood cancer treated with doxorubicin from healthy control subjects . Echocardiographir data from the experimental group of 21 patients (mean age 16 t 5 years) treated from 1 .6 to 14,3 years (median 5 .3) before this study with 27 to S32 mg/m' of dosorubicin (mean 196) were compared with echocardklgraphic data from 12 normal age-matched control subjects . Graded dobutamine infusions of 0 .5, 2.5, 5 and 10 pg/kg per min were administered . Echorardiographic Doppler studies were per, formed before infusion and after 15 min of infusion at each rate . Dobulamine Infusion at 10 pglkg per min was discontinued after six studies secondary to a 50% incidence rate of adverse symp , terns. The most important findings were that compared with values In control subjects, end-systolic left ventricular posterior wall dimension and percent of left ventricular posterior wall thickening in doxorubkhe4reated patients were decreased at baseline study and these findings were more clearly delineated with dobutamine stimulation . End-systolic left ventricular posterior wall dimension at baseline for the doxorubkia-orated group was Il s 1 .9 mm versus 13.1 z 1 .5 mm for control subjects (p < 0 .01) . End-systolic left ventricular posterior wall dimension at the S-pg/kg per min

dobutamine infusion for the doxorublein-treated group was 14 .1 t 2.4 mm versus 19 .3 s 2.6 mm for control subjects (p < 0.01). Percent left ventricular posterior wall thickening at baseline for the doxorubieles-treated group was 78 t 18% versus 97 t 13% far the control group (p < 0.01). Percent left ventricular posterior wall thickening at itte 5-p/kg per min dobutamine infusion for the doxorubicin-treated group was 121 € 37% versus 185 € 20% for the control group in < 0.01). Decreased left ventricular shortening fraction and Increased left ventricular end-systolic meridional wall stress were demonstrated in doxorubkin-treattd patients only during dobatamine infusion . No differences were found between results in control subjects and deco ublcin-treated patiens for measured diastolic variables. Thos, usymptom ate long-term survivors of childhood cancer treated, with doxorubicia may have latent decreased cardiac performance That is undetected by community used echucardlographic methods, Including rest left ventricular xhneOning fray

Doxorubicin (Adniamycin) is a widely employed and effective chemotherapeutic agent, but dose-related cardiotoxicity limits its usage (1-10). Numerous noninvasive methods . including radionuclide angiography and echocardi braphic assessments of systolic and diastolic function (10-19), have

been utilized to detect subclinical doxorubicin-induced cardiomyopathic changes. Dobutamine stress echocardiography was recently reported (20) to be an accurate noninvasive diagnostic technique for detecting cardiac dysfunction in adults with coronary artery disease . Our purpose was to determine if inotropic challenge with dobutamine could unmask in asymptomatic doxorobicin-treated long-term survivors of childhood cancer echocardiographic abnormalities in cardiac function not present in healthy normal control subjects .

From the University of Arizona College of Medicine and Steele Memorial Children's Research Center. Tucson. Arizona. This study was supported

by

the Pediatric Cardiology Research Fund . the Cancer Research Fond . and the National Institutes of Health Short Term Research Training for Students in Health Professional Schools . University of Arizona College of Medicine . Tucson . Arizona . Manuscript received May I, 1991 : revised manuscript received August 28. 1991 . accepted September 6, 1991 . Mdress for eondnts : Stanley I . Goldberg, MD. Department of Pediatrics (Cardiology). University of Arizona College of Medicine, 1501 Noah Campbell Avenue, Tucson, Arizona 85724 . 01992

ton goad left ventricularend-systetk merludlmW

wao stress.

Our

data establish that evaluation of eD ventricular systolic fe canon by end-systolic posterior woll dimension, posterior wall thickening, rod-systolic merHbnat

wall

stress and shortens g fraction

measured during laotropic stimulation with dohutmtdae provides a sensitive technique far examining the cardiac status of asymptomatic doxo ubkiu-treated patients . (J Am Coil Cardiaf 1991;/9;394-401)

Methods Study subjects. The study group consisted of children and young adults previously treated with doxorubicin at our

by The American College of Canho!ogy

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0775-109719051 . a1

IACC Vol. 19 . N9 . 2 Fesmary 1992 .394-4111

KLEW ER ET AL . CARDIAC EVALUAtoON BY DOROTAMINE ECHOCARDIOGRAPHY

institution for childhood cancers. Control subjects were healthy normal siblings of the doxorubicin-treated group or age-matched volunteers . Subjects gave informed consent . and if the subject was a minor, parents also gave consent according to a protocol approved by the institutional Human Subjects Committee, Because the objective was to evaluate asymptomatic doxorubicin-treated patients. patients with congenital heart disease, cardiac failure and arrhylhmias and those taking cardiac medications were excluded . Pregnancy in patients and control subjects was excluded by urine beta-human chorionic gonadotropin test . Standard measurements. Age . height and weight were obtained and body surface area was computed (21) for each subject. During the period of study, heart rate aid rhythm were monitored continuously ; bled pressure was measured every 5 min by sphygmomanometry . Echncardlography. Echocardiographic examiners were unfamiliar with the clinical states of the subjects . The heart was imaged with a Biosound ND256-8 or Hitachi CVC-151 echocardiographic system . A baseline two-dimensional echocardiohraphic assessment was performed to rule out structural heat, disease . Parasternai shun-axis view-, of the left ventricle were imaged to assess symmetry of contraction (16) . M-mode echocardiograms of the left ventricle from the parastemal short axis were recorded in a standard manner (22).. gain was adjusted initially to reveal only pericardia! mahon, then gradually increased to image left ventricular posterior wall motion . Apical four-chamber planes that provided good visualization of the mitral anutus and leaflets were obtained by placing subjects in the left lateral decubitus position. With the subjects in this positron, Doppler examination of mitral flow velocity was performed with the rangegated pulsed Doppler technique; the ultrasourd beam was aligned as parallel to flow as possible with the sample volume positioned at the tips of the mitral leaflets . From this position it was also possible to record a diminished amplitude of aortic valve closure for measurement of left ventricular isovolumetric relaxation time . Recordings were registered at the rate of 100 min/s . Doppler flow velocity in the ascending aorta and aortic diameter for computation of aortic flow were obtained from the suprasternal notch by using a 25° off axis transducer designed for this purpose (23) . Dobutamine infusion. After baseline recordings were obtained, continuous dobutamine infusion was initiated at 0.5 ,ag/kg per min and increased to 2 .5, 5 and 10 pg/kg per min. To attain steady state dobutamine concentration, dobutamine was infused at each rate for 15 min before echocardiographic examination (24) and the echocardiogram was performed between the 15th and 20th min . The infusion rate was increased after completion of the Doppler echocardiographic studies at each dobutamine dose . Dobulamine infusion was terminated because of any of these complications : I) arrhythmias ; 2) an increase in blood

pressure >30% above baseline values or a decrease to >20% below baseline ; 3) an increase in heart rate >40% above baseline ; and 4) significant subject discomfort or anxiety .

395

Echocardiographic measurements, Left ventricular cavity and posterior free wall dimensions at end-diastole (LV ro and LVPW EO) and end-systole (LVES and LVPW ES) were measured in cm according to American Society of Echocardiography criteria (22) with an average of 3 to 5 cycles reported . Left ventricular shorts ing fraction (SF) was computed according to the method of Gutgesell et al . (25) with the equation SP =

loo%

x ILVEn - LVES)ILVEO .

Left ventricular posterior wall percent chickening (%,LVPW,mek,,,;ra), which is independent of body surface area (26), was calculated by this equation : 7.LVPW

4 = 10017, x ILVPWES - LVPWc0)/LVPWea .

Left ventricular end-systolic meridional wall so, .ss g/cm2 was calculated according to the method (ESsraess) in of Grossman et al . (27,28) with use of this equation : ESSwess = [I 1 .35)(MBP)(LVc

)1 / [(4)(LVPWES)(I + LVPWESILVES)) ,

where MBP = mean blood pressure as an estimate of end-systolic pressure in mm Hg and 1 .35 is the factor to convert pressure from mm Hg to g/cm 2 . Mean blood pressure was estimated by the equation MBP = (2DBP + SBP)/3 . where DBP = diastolic blood pressure and SBP = systolic blood pressure . Left ventricular isovolumetric relaxation time was measured with a digitizer at a 1Gsolution of I ms from aortic valve closure to the first upstroke of diastolic mitral flow velocity . Mitral deceleration time was measured from the peak of the mitral inflow wave to the point where the extrapolated deceleration velocity crossed baseline. Peak mitral E and A wave filling velocities were measured according to the method of Nishimura et al . (29) . Ascending aortic flow was measured and computed by the method of Locher et al. (30) with an average of 9943 cycles reported. Angular correction was not used because alignment with flow in all planes was possible. Statistical analysts . Data for the study group were compared with those for the control group by using the unpaired Student r test . Simple linear regression was utilized in the experimental group to assess the relation between echocardiographic measurements and doxorubicin cumulative dose, age during doxorubicin treatment and time since last doxornbicin dose. All data are reported as mean values t SD.

Results Study subjects (Table 1) . The control group was composed of 12 normal, healthy subjects (9 male, 3 female) aged 10 to 22 years (mean 18 € 4) . The study group consisted of 21 patients (12 male, 9 female) aged 9 W dl years (mean 16 t 5) who had been previously treated with doxorubicin for a variety of childhood neoplasms . Cumulative doxorubicin

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396

Kf.FWERFTAL. CARDIAC EVALUATION BY DDLGTAMINE ECIIOCARDIOGRAPHY

IACC Vel . 19 . Nu. 2 February 199291/-401

Table 3 . Doxorubicin Patien! Data' Do . .rubicin Patient No.

Age (yrV Gender

WI lkgl

H: (cm)

BSA (roc)

Cancer Type

Total Dose (mg/ml)

Age (yr) During Rx

Tin, (yrl Sire. Ra

13 14 I5 16 17 18 19 20 21 220 23 24 25 26 27 28 19 30 31 32 33

22/F 12/F 13Rd 17/1' Ill/H 10/,0 10117 9.94 20/51 13,711 12311. 121F 13117 19'F 15/1, 161F 21/M 27/M 21194 2WM 91M

52 48 51 51 35 62 43 45 76 79 4' 49 59 71 39 62 52 89 62 66 34

16' 144 144 154 IM 144 142 145 /60 163 144 146 156 163 146 164 161 189 156 170 136

1 v 1 .36 1 .4 1 .47 1 .16 1 .52 1 .29 1 .34 1 .85 1 .85 1.28 1 .39 1 .58 1 .77 1 .26 1 .67 1 .53 2 .16 161 1.77 1 .13

ALL Ewing Wilms 0veo NHL Hodgkin ALL ALL ALL Hodgkin ALL ALL ALL ALL ALL 0srer ALL NHL NHL ALL ALL

27 61 86 100 too 104 194 110 120 121 168 172 183 232 238 242 242 1 6, 425 489 532

154 1o 3 .3 14 .6 4 .9 79 5 .8 4 .3

7.3 23 10.3 2 .4 5 .3 2 .4 4 .3 5 .6

108

10

11 .1 8A 5 8 .5 15 .3 59 19.8 131 15 7.2 183 75

18 4 .1 7 .9 5 .1 4 .3 9.8 5 .6 9.1 171 14.3 2.6 1 .6

'Clinical details of patients previously treated wish doxambicin for cancer in childhood . Patient numbers correspond to the patient numbers in Figure I (Subjects 1 to 12 are control subjects). Patients are listed in order of increasing doxombicin dose . tRaOenl 22 received 2,040 rods of mediasttnal inadutiun. ALL = acme lymphoblastic leuk :mia BSA = body surface area : Ewing = Ewing sarcoma ; Hodgkin = Hodgkin disease; Ht = height : NHL = non-Hodkkins lymphoma ; Octeo = oitso,anewus: Rx = treatment. Wilms = Wilms tumor ; Wt - weight.

doses ranged from 27 to 532 mg/m7 (mean 196 s 137) . The the first six studies (four in patients . two in control subjects). time elapsed since the last dose of doxorubicin ranged from At this infusion rate three of the six subjects met exclusion 1 .61o 14 .3 years (mean 6 .1 € 3.6, median 5.3). criteria, including initiation of ventricular bigeminy in a Dobutamine dose . Administration of 10 pug/kg per min of control subject, premature ventricular and atria) complexes dobutamine as part of the protocol was discontinued after in one study patient and choking, sweating and shortness of

Table 2 . Hemodynamic Results in 33 Subjects' Dobutamine Dose Ha on line Doxmubicin Control 0.5 0038 per min Duaomhicia Control 2.5 icglkg per min Doxombicin Control 5 pglkg per min 13oxumbtein Control 10 pg/kg per min Doxombicin1 Controls

HR Ibeatslmin)

in

MBP . Hg)

CI (liters/min per m 2 1

SVI imVbeat per mi t

66 0 9 66 x 16

91 _ if. 84 x 8

4 .5 < 13 4 .6 1 1 .2

69 x 19 72 x 16

66 0 9 65 0 18

84 x 9 85 0 8

4 .9 0 1 .4 5 - 1 .3

74 - 20 77 0 153

67 _ 9 64 x 19

88 x 9 88 9 '

5 .5 o 1 .3 5 .3 x Ll

82 _ 20 83 ° '5

71 67

0

11 17

90 0 9 92 x 8

5.9 - 1 .5 6 - 1 .5

83 z 20 91 : 16

98 88

0

13 3

90- 5 90 0 2

7.1 x 1.3 7.7 0 3.5

73 - 14 88 x 3

0

t

'Summary of hemodynamic data in doxombieimtreated patients In = 211 and control subjects (n = 12) at rest and during dobutamine stress lest . No statistically significant diifenences were found between the dox0mbicin treated patients and control subjects . Values are mean values 4: I SD. In = 4; to = 2 ; CI = cardia, index ; HR = heat rate. MBP = mean blood press- SVI = stroke volume tries .

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IACC Vol. 19. No . 2 Febrvary 1992 :394-401

KLEWER ET AL. CARDIAC EVALUATION DY DORUTAMINE ECHOCARDIOGRAPHY

397

Table 3. Dobutamine Stress Echcca :dograpoy Results*

Dobutannne Dose 0aselmo Doxonlbi•m Control 0 .5 py'kg per in Doxorubaln Canvnl 2 .5 pgAg per in Dcxorubicin Control 50 tokg tier min Doxomhicin Control 10 04/kg per min Dnxombwint ('mural

SF

/'. V°WTH

LVESS (Wed)

LVPWES In .)

I VPWED (mrnl

IVRT (in"

MDT (ms)

E (rm!wl

(-10

NA min

-_0 34 0.05 0 .37-005

78 n 181 97€I3

68 ' 21 56- '4

II € 19* Iii-1 .5

6 .2 € 1 1,7€0.9

60 0 12 58 10

167 € 30 160€29

61 -t. 22 770 II

30 € 10 38 x 11

2 .1 € 0.4 21€0.4

0 .37 ' 1.0b 9 .39€0.07

WI ' '_17 127 23

58 e 17 46€ It

11 .9 ' 21 14.E_2

6' 6

53 € II 56!10

171 ' 25 165x24

65 0 23

71x24

33 € 11 37€11

2 + 0.4 2.200 .6

041 0 0 .00 0.46

112 € 321 155-1h

SO n 191 36'9

13 .1 2 .Y 17 .1'2 .1

6.3 : 1 67

50 x i2 4908

159 . 28 158x28

69 € 191 89!21

32 ' 81 39€9

2 .1 € 03 2 .350.4

0.45 € 0 .061 9.51 € 0 .05

121 0 377 185 _ 20

47 € 171 28 18

14 .1 € 24t 1'; ' _ 2 6

6.5 1 .3 6 .8 + 0 8

42 0 11 47 ' 9

142 € 30 155 5 31

81 *- 27 98 x 26

39 € 14 44 € 12

2.2 € 0.5 2.3 € 0.4

0.44 . 011 053 -- 003

91 € /0' 1N - 20

40 € 191 17 _ 2

1

6 .6 € u.8 6 % - 114

34 € !8 157 ! 53 78 € 36 51 € 32 1 .7 € 0.3 49 € 18 77 0 9 2.1 + 0 .5 132 ' 5 36 ! 4 tp < 'Unless otherwise ooAd, u = 21 doxomEdn-veered paliests and 12 wmrol subjects, 0,01 and Sp < 0.05 relative to vala .- in control subjects . $n = :2s + 2 .61 16 .8 ' 04

4; I n = 2 . Values are mean values € SD . A = morel flow velocity at the time of auial ccm :e,on . 0 = initial peak mar.' flow velocity : FJA ratio = ratio of peak mural Bow velocity to mural flow ve:ocity at the time otatnal coerraclion . IVRT = is volumetric relaxation time ; LVESS = end-systolic wall stress ; LVPWED - left ventrcular eud ,diastolic posterior wail thickness; LVPWES = left ventricular end-,yuoIw pus' anion wall mwkness; MDT = mural deceleralion time . 7tLVPWrt1 = percent left -I-b, posenor wall Ihick.ning; SF - shaite.mg trot-. .

67 . 15 kg for the control group (p = 0 .05). Mean body surface area was 1 .52 `. 0.26 m 2 for the study group and 1 .76 € 0.27 ns for the control group (p = 0.02) . Hemodynamic data are summarized in Table 2. echocardiographic measurements (Table 3). Figure I shows standardized changes in echocardiographic measurements and Figure 2 demonstrates individual changes from

No arrhythmia, symntems or other exclusion criteria were encountered at the lower infusion rates in any study subject . Standard measurements . Age was not significantly different between the groups. Mean height was 154 t 13 cm for the study group and 168 € 14 cm for the control group (p = 0 .008) . Mean weight was 56 € 15 kg for the study group and breath in another.

o --

zoo -

0

c o e

Flame 1 . Standardized percent left ventricular (LV) posterior wall (PW) thick-

o 'y 0 il0o- • • "0 son e e ao 0 0 0° a .. - _ . . 00 0 00 Q ° ° a0 0 _In* _ su o TI 1 1 1 1 i° 1{{ 1 1 1 1 1 1 1 1 1 1 1 1 1 1 120 -

ening, end-systolic wall stress and percent shortening traction at baseline (kill =~ 60= m and during the 5-N4/kg per min dobutamine infusion (right) for each subject . Dashed lines indicate € 2 SD of control data . Control subjects (n = 12) are marked by solid squares; doxombicin0 treated padenis (n = 21) are marked by 60 open diamonds and are listed in ase-ndT ing order of cumulative doxorubicin dose 50 as in Table I .

•

0 0

-

o

--- o 1 I

I

I

I

I

I

1

I

. .

• •°

00 oo°oo

00 o°ac°o

0

00 0 O

O

0 °00 ° 00 • 0000 - - - - - -O . -0- 2 -9O r 10 1 1 1 1 1 1 1 1 1 1 ' l l 1 1 1 1 1 1 0 3 6 9 ,'e 15 IC 21 24 27 30 33 0 3 6 9 11 15 16 21 24 27 30 33 •

30 ~'~

0 o °

- I I I I I I I I I I I - - - - -- - - - - - - - _ -

0-no-

O o

5ublect oember

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Subject number





CLEWUU UT AL . CARDIAC EVALUATION BY LK)BUTAMINE EC71(XARDIOGRAPHY

398

W C

IACC Vo1 . 19, No . 2 pebnary 1992:790-001

200

I

d

uP r i >

'oo-

J

e 0

0

Jo III Figure 2. Data for percent left ventricular posterior wall thickening, shortening fraction and end-systolic wall stress for control subjects and doxombicinueaied paients plotted by each subject s baseline values . The solid bar depicts the baseline value and the iwtcbrd Iran depict . !he value during the 5-µg'kg per min ddaotnbi_ia ~.nfasion . Abbreviations as in Figure I .

N E

120 *00-

a N m

N m

80 -

3

o

ao

y C W J

Controls

Treated Patlenta

baseline values . End-systolic left ventricular posterior wall dimension and percent left ventricular posterior wall thickening were the must consistent factors for differentiating study and control subjects at rest and during each dobutamine infusion . Individual changes in percent left ventricular posterior wall thickening from baseline to peak dobutamine stress were statistically decreased in the doxorubicintreated patients when compared with changes in control subjects (44 € 27% vs. 88 € 21%r) (p < 0 .01). The mean left ventricular shortening fraction in doxorubicin-treated subjects was not different from that in control subjects at rest

but demonstrated significantly lower (r < 0.05 and p < 0 .01) values compared with those of control subjects receiving moderate doses (2 .5 and 5 ;.tg1kg per min, respectively) of dobutamine . Individual changes in left ventricular shortening fraction front baseline to peak dobutamine stress were not significantly different in the doxorubicin-treated group when compared with changes in the control group (0 .12 0 .05 vs. 0.14 € 0.07). Mean end-systolic stress was significantly higher (p < 0 .01) at dobutamine infusion rates of 2 .5, 5 and 10 µglkg per min in the doxorubicin-treated group compared with mean

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KLEWER ET AL, CARDIAC EVAI .IIATIDN BY D09UTAMINE ECHOCARDIOGRAPHY

JA CC Vol. 19 . No. 2 February 1992 .994-401

Table 4 . Relation of Dose Results to Doxombicin Treatment History' Dobwam,ne Infu4on Sale lµp'kg per mint 11aeeline

0 .5

2 .5

5

doss

0-2 0.12 412

0 .26 0' 11 022

0 .08 0 .05 0 .13

03 11-05 0 .1 ;

Total dotornbiem dose Age dung lie Time since Rx LVE55 Total doxorubicin dose Age dur'ag Rx Time since Rx

0.07 024 11112

0 .03 0-!2

oat

0 .16 0.24 0101

a .21 (,!!I

0.17 0.1 019

0.24 O. V,' 0 .24

0.31 0.16 0 .25

0 .26 li. R 0.1

SF To al doxowbicin Age during Rr. [ .me ce Rx 7.LVPWIR

'Correlation values U1 for simple linear regressiml analysis of echocardiographic measurements versus cemulalive doxorubicin dose, age at Ome of dotanrbicin tr. .-nent and lime elapsed sine, Izsl doxurubi,r: : treatment . No correlation was statistically significant . Rx therapy . other abbreviations as in Table 3.

values in the coutroi group . Individual changes in left ventr c . ular end-systolic meridional wall stress from baseline to peak dobutamine stress were similar for doxorubicin-treated patients and control subjects (-21 t 13 vs . -28 t 13 gfcm2 ) tp = NS) . Individual subject data for percent left ventricular posteriorwall thickening, shortening fraction and end-systolic stress at baseline study and at the 5-µgfkg per min dobutamine infusion rate are plotted in Figure I . Mean mitral E and A flow velocities at the 2 .5 p4tg per min dobatamine infusion rate had significantly greater amplitudes (p < 0.05) in the control group than in the study group, but the mean mitral E to initial A ratio at this level did not differ significantly between the two groups . Heart rate, mean blood pressure, indexed cardiac output and stroke volume, end-diastolic left ventricular posterior wall dimension, left ventricular isovolumetric relaxation and mitral deceleration times, and the ratio of mitral E to mitral A velocities were not significantly different when mean study patient and control subject data were compared at baseline or at any level of dobutamine infusion . Relation of echocardiographie measurements to doxorubicin treatment history (Table 4) . No echocardingrnphic measurement was significantly related to total doxoruhicin dose, patient age at time of treatment or time elapsed since doxorubicin treatment at rest or at any dobutamine infusion level . Correlation values for variables found to be significantly different from control values (shortening fraction, percent left ventricular posterior wall thickening and left ventricular endsystolic meridional wall stress) are shown in Table 4 . Discussion Decreased end-systolic left ventricular free wall dimension and percent posterior wall thickening, a measure that

3 99

reduces dependence or, body surface area (26), were the most sensitive indicators of prior doxoruhicin exposure . Decreased shortening fraction and increased left ventricular, end-systolic wall stress, indexes that are reported to become markedly abnormal with clinical doxorubicin-induced congestive heart failure (31-34), were demonstrated only during moderate dose dobutamine infusions in our asymptmnatic study group . End-diastolic left ventricular free wall dimension was not significantly different between the two groups ; such a difference might be expected if substantial myocardial fibrosis were present in the doxorubicin-treated patients. Doxorubkin cardiotoxicity . Doxorubicin cardiotoxicity has been recognized for almost 2 decades (1) . Dose-related cardiotoxicity occurs in most patients as demonstrated by abnormal endomyocardial biopsy findings (2-6) . Early histopathologic changes include cardiomyocytn sarcoplasmic reticulum swelling, myofibrilisr dropout and cytoplasmie vacuolation . These changes may progress to diffuse myocyte damage and frank necrosis . Hisiopathologic changes precede clinical myocardiopathy (2-6,10) . In most patients ;ome deterioration in cardiac function is shown by noninvasive techniques during doxorubicin treatment (10-13) . Generally, improvement does not occur during the year after treatment with doxorubicin, although some exceptions are reported (9,32) . Invasive endomyrcardial biopsy studies in doxorubicintreated patients have demonstrated that higher doses of doxorubicin are more frequently associated with clinically apparent cardiatoxieny . However. some patients tolerate maximal doses without acute toxicity ; others develop congestive heart failure at relatively low doses (3,5) . A high cumulative doxorubicin dose, a longer interval since completion of doxorubicin therapy, and age 5 years after doxombicin treatment. Goorin et al . (33) reported that patients whose first episode of clinical congestive heart failure developed >6 years after completion of doxombicin therapy maintained appropriate left ventricular internal dimcnsioi,.s with somatic growth but had diminished left ventricular systolic free wall dimension . These investigators postulated that the resultant elevated wall stress contributed to a reduction in left ventricular performance and to congestive heart failure (33) . Lipshultz et al. (34) reported similar findings in 115 patients treated I to 15 years previously with doxombicin for acute lymphoblastic leukemia . They hypothesized that loss of cardiac myocyles during doxombicin therapy in childhood might result in inadequate left ventricular mass and clinically important heart disease in later years . Our asymptomatic doxombicin-treated patients had a significantly diminished end-systolic left ventricular free wall distension at rest . However, the mean difference between doxombicin-treated patients and control subjects was only 2 mm . Diminished end-systolic left ventricular free wall dimension in the doxcrubicin-treated group was more clearly demonstrable during dobutamine stimulation (14 .1 € 2.4 cm for the doxombicin-treated group vs. 19.3 . 2 .6 em for the control group at 5 jag/kg per min of dnbutamine) . Rationale of method of dobutamine testing . Dynamic stress testing has long been used to detect occult cardiac dysfunction in adults with coronary artery disease (39) . Recently, pharmacologic stress echocardiography using dipyridamole, adenosine and dobutamine has been utilized . Dobutamine is a relatively short-acting beta, agonist with primarily inotropic action at low doses and it seems an ideal drug for studying cardioselective responses to catecholamines. Dobutamine stress echocardiography using graded dobutamine infusions of 5 to 40 µglkg per min has similar diagnostic accuracy in coronary artery disease to that of other proved methods (20,40-42) . Generally, dobutamine infusion is increased in 2- to 3-min increments until clinical end points are attained . To clearly delineate hemodynamic responses at each dobutamine infusion rate, we evaluated cardiac function when plasma dobutamine concentrations were at steady state, after 15 min of infusion at each infusion rate . Our data suggest that a dobutamine infusion rate of 10 Aglkg per min is associated with a high incidence (50%) of adverse effects in asymptomatic children and young adults . Furthermore, the 15-min dobutamine infusion at 5 yegiikg per

min was safe and useful for effective isotropic stimulation in our subjects. Accounting for differences In body size . Oor doxorubicintreated patients were similar in age to the control group but were significantly shorter and lighter in weight . Size differences between study patients ant control subjects occurred because 1) the objective was age matching, 21 the male to female ratio was higher in the control group, and 31 some of the study patients had been treated with corticosleroids . resulting in diminished growth potential, Accordingly . echocardiographic measures that are not dependent on body surface area were used to assess cardiac function . Limitations, The present investigation had cc it- n limitations . Our youngest study subject was 9 ;ears old; therefore we cannot comment on the suitability of thl : test for younger cancer patients . The clinical implications of these echocardiographic findings are not clear because we do not have long-term cardiac follow-up data on these patients . Future evaluation of the clinical status in these currently osymptomatic doxorubicin-treated patients will be essential . Conclusions. Asymptomatic doxombicin-treated patients may have cardiac damage undetected by commonly used methods. End-systolic left ventricular free wall dimension and percent left ventricular posterior wall thickening were decreased in doxorubicin-treated patients at rest compared with values in control subjects, but dobutamine infusion magnified these differences . Other rest echocardiographic measures of systolic and diastolic function were similar for asymptomatic doxombicin-treated patients and control subjects . h: particular, shortening fraction and end-systolic left ventricular wall stress were abnormal only during isotropic stimulation in our asymptomatic doxombicin-treated group . Percent left ventricular posterior wall thickening and endsystolic left ventricular meridional wall stress appear to be more sensitive than shortening fraction for differentiating individual doxorubicin-treated patients from control subjects during moderate inotropic stimulation with dobutamine . Our data suggest that dobutamine stress echocardiography is a useful noninvasive technique for examining the cardiac status of doxombicin-treated patients, and should be considered for monitoring these patients on a long-term basis .

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JACC

Vol. W. No . 7

Fcrmary l097,a4_ 401

KLEWER

ET A[ . .

401

CARDIAC EVALUATION HY DOBUTAMINE ECHOCARDIOGRAPHY

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