anthracyclines are the most frequent cause of iatrogenic congestive heart failure ranging from acute reversible minor to irreversible reduction in the left ventricular ( lv ) ejection fraction and death despite preventive measures .
serial surveillance for cardiotoxicity in patients receiving anthracyclines has most commonly centered on the assessment of lv systolic function by standard echocardiography .
the development of new quantitative echocardiographic techniques , such as ultrasonic strain ( s ) and strain rate ( sr ) imaging , has enhanced our ability to noninvasively assess regional myocardial function .
we investigated the lv function , using doppler derived s and sr imaging , in long - term survivors affected by acute lymphoblastic leukemia ( all ) treated with a low cumulative dose ( 210 mg / m ) of anthracyclines , and in presence of a normal global lv systolic and diastolic function , as assessed by standard echocardiography .
the study population was recruited between january 1983 and december 1990 at the pediatric oncology service of second university of naples and studied at the pediatric cardiology outpatient clinic of the same university .
all patients were affected by all : of the original 112 patients diagnosed in that period , 44 were excluded because died of disease , 30 declined the invitation to undergo echocardiogram , and 16 were excluded for inadequate echocardiogram .
the remaining 21 patients , who were in continuous remission , presented no cardiac symptoms , have been treated with a low cumulative dose of anthracyclines ( 210 mg / m ) , and had received the last dose at least 10 years previously , were considered eligible for the study . in this group ,
mean age at diagnosis was 3.6 years ( range 1 - 11 years ) and the mean of follow - up interval from last dose of anthracycline was 15.7 years ( range 11 - 20 years ) .
the mean cumulative dose of anthracylines was 180 mg / m ( range 120 - 210 mg / m ) .
all patients were recruited in associatione italiana ematologia - oncologia pediatrica - all protocols . in detail , 1 patient
was enrolled in 8201-protocol ; 5 patients in 8202 protocol ; 12 patients in 8702 protocol ; and 3 patients in 8703 protocol .
the control group consisted of 21 healthy subjects , comparable for age and sex . all patients and controls gave written informed consent to participate in the study .
both the standard echocardiographic study and the color doppler myocardial imaging ( cdmi ) data were digitally stored and all the measurements were performed off - line by 2 independent observers who were blind to the clinical status of the subjects .
the standard echocardiographic study has been performed following a standard methodology . the myocardial performance index ( mpi ) , defined as the sum of isovolumic activity ( isovolumic contraction time and isovolumic relaxation time ) divided by ventricular ejection time ,
all cdmi data were acquired at a frame rate of 220  15 frames / s ( ge vingmed system seven ; 3.5 mhz ) .
the normality kolmogorov - smirnov test was performed to determine whether continuous variables were normally distributed .
a comparison between groups of continuous variables was performed by using the student 's t test , whereas skewed distributed variables were compared by using the rank mann - whitney u test .
categorical variables were compared by using the chi - square test . a p value < 0.01 was used to reject the null hypotesis .
all the analyses were performed using a commercially available package ( spss , rel 11.0 2002 .
the normality kolmogorov - smirnov test was performed to determine whether continuous variables were normally distributed .
a comparison between groups of continuous variables was performed by using the student 's t test , whereas skewed distributed variables were compared by using the rank mann - whitney u test .
categorical variables were compared by using the chi - square test . a p value < 0.01 was used to reject the null hypotesis .
all the analyses were performed using a commercially available package ( spss , rel 11.0 2002 .
clinical and standard echocardiographic characteristics of the studied sample ivsedd = interventricular septum end - diastolic dimension , pwedd = posterior wall end - diastolic dimension , ef = ejection fraction , dt = deceleration time , ivrt = isovolumic relaxation time , mpi = myocardial performance index , all = acute lymphoblastic leukemia the normal children did not significantly differ from patients in age , sex , heart rate , and blood pressure . both groups had similar standard measurements of lv systolic and diastolic function ( lv ejection fraction and mitral e / a ratios ) .
the lv mpi in the study patients was not statistically different from that of normals [ table 1 ] .
longitudinal s and sr were similar to those measured in healthy subjects [ table 2 ] .
peak systolic longitudinal strain values ( % ) of the studied sample a4c = apical 4 chamber view , all = acute lymphoblastic leukemia radial s ( 17  3% vs. 55  6% , p
< 0.0001 ) and sr ( 2.1  0.3 vs. 3.0  0.8 1\s , p < 0.0001 ) , assessed on the midsegment of the posterior wall from the parasternal views were significantly reduced when compared to healthy subjects [ table 3 ] .
one patient ( 5% ) had both peak systolic radial s and sr < 2 sds below the mean of normal subjects .
peak systolic radial strain and strain rate values of the studied sample sax = parasternal short axis view , plax = parasternal long axis view , all = acute lymphoblastic leukemia
doppler derived s and sr indices unmask early systolic abnormalities in long - term survivors of all treated with low cumulative dose of anthracycline .
radial myocardial deformation is involved in systolic dysfunction , while longitudinal myocardial deformation is normal .
this finding may seem surprising since in several cardiac disease ( coronary artery diseases or valvular heart diseases ) longitudinal dysfunction generally appears very early as the first stage of subclinical myocardial damage , in contrast radial strain deteriorates later when ejection fraction starts to decrease .
the possible explanation of this earlier radial functional deterioration may be related to the different mechanism leading to cardiac dysfunction in in long - term survivors of all treated with anthracycline .
indeed , oxidative stress plays a major role in anthracycline - induced cardiomyopathy , stochastically involving myocites .
the longitudinally directed fibers compose only a small portion of the myocardial mass , while myocardial fibers responsible of the radial function are quantitatively more represented , and thus more exposed to oxidative damage . on the contrary in coronary artery disease or valvular heart disease the subendocardial layer , responsible of longitudinal function ,
significant abnormalities of s and sr occurred in presence of normal standard echocardiogrphic doppler measures of lv systolic or diastolic function .
these changes occurred at cumulative dosages as low as 100 - 210 mg / m . in our sample , only four patients had a cumulative dosage between 200 and 210 mg / m . of note ,
this finding is in agreement with previous report demonstrating that mpi is able to detect changes in global myocardial function in presence of a cumulative dose of antracycline  200 mg / m . in this preliminary study
, the myocardial deformation indices appear to be a more sensitive noninvasive technique for detecting subclinical lv dysfunction than other echocardiographic measurements .
thus , we are limited by angle dependency and we can only assess radial function at the level of the midsegment of the posterior wall .
for the same reason , reliable cdmi data were obtained in all patients from the apical 4 chamber view , while relible data were obtained only from 80% of our patients in apical 2 chamber view .
conversely , color doppler derived imaging is the only way to fully resolve sr which is less load dependent compared with s.
thus , we are limited by angle dependency and we can only assess radial function at the level of the midsegment of the posterior wall .
for the same reason , reliable cdmi data were obtained in all patients from the apical 4 chamber view , while relible data were obtained only from 80% of our patients in apical 2 chamber view .
conversely , color doppler derived imaging is the only way to fully resolve sr which is less load dependent compared with s.
 we investigated the left ventricular ( lv ) function , using for the first time strain ( s ) and strain rate ( sr ) imaging , in long - term survivors affected by acute lymphoblastic leukemia treated with a low cumulative dose of anthracyclines , and in presence of a normal global lv systolic and diastolic function . 
 a total of 21 were enrolled in the study . 
 the mean cumulative dose of anthracylines was 180 mg / m2 ( range : 120 - 210 mg / m2 ) . 
 as control group 21 age - sex matched healthy subjects were included . 
 radial s ( 17  3% vs. 55  6% , p 
 < 0.0001 ) and sr ( 2.1  0.3 vs. 3.0  0.8 1\s , p < 0.0001 ) , assessed on the midsegment of the posterior wall from the parasternal views were significantly reduced when compared with controls . 
 conversely , myocardial performance index was not able to discriminate between patients and controls . in this preliminary study 
 , the myocardial deformation indices appear to be a more sensitive noninvasive technique for detecting subclinical lv dysfunction than other echocardiographic measurements . 