Journal of Cancer Therapy, 2011, 2, 161-166
doi:10.4236/jct.2011.22019 Published Online June 2011 (http://www.SciRP.org/journal/jct)
161
Early Diagnosis of Cardiac Toxicity Related to
Antineoplastic Treatment
Maria Maiello1, Rakesh K. Sharma2, Marco Matteo Ciccone3, Humananth K. Reddy4,
Pasquale Palmiero5*
1Cardiology Department, ASL BR, Brindisi, Italy; 2Cardiology Chair, University of Arkansas for Medical Sciences, El Dorado, USA;
3Cardiology Chair, University of Bari, Bari, Italy; 4Clinical Professor of Medicine, University of St. Louis, Associate Medical Director
Medical Center of South Arkansas St. Louis, Arkansas, USA; 5Contract Professor of Cardiology, University of Heart Station,
Brindisi, Italy.
Received April 13th, 2011; revised May 23rd, 2011; accepted May 31st, 2011.
ABSTRACT
Background: breast cancer because of radiotherapy and/or chemotherapy causes cardiac disease, often it occurs on
women just affected by hypertension and/or diabetes. All these conditions may affect left ventricular (LV) geometry,
mass and diastolic function. The purpose of this study is to early detect these affections to improve heart failure preven-
tion. Patients and methods: 134 women, affected by breast cancer, underwent to conventional transthoracic echocar-
diography (TTE) and pulse wave tissue Doppler imaging (PW-TDI). A control group (CG) of 80 women unaffected by
breast cancer, hypertension and diabetes was enrolled. Results: 54 of 134 women (40.2%), were affected by hyperten-
sion or diabetes too (Prone Group = PG), 8 by both, 80 (59.8%) were free (FG). Mean age of all patients was 45.4
years. The rates of LV eccentric hypertrophy and LV distolic dysfunction were statistically significant higher on FG
group than controls, and on PG group than FG group. Conclusions: an abnormal LV diastolic function is more com-
mon among women affected by breast can cer after treatment than in general population , the same for LV eccentric hy-
pertrophy but at a lower rate. 40% of women were affected by hypertension, diabetes or both, and as expected they
have a higher rate of LV eccentric hypertrophy and diastolic dysfunction. This high prevalence of LV eccentric hyper-
trophy and diastolic dysfunction, on asymptomatic women, affected by breast cancer, is a predictor of heart failure;
Doppler-echo techniques may be helpful in early diagnosis.
Keywords: Breast Cancer, Radiotherapy, Chemotherapy, Hypertension, Diabetes, Left Ventricular Geometry, Left
Ventricular Mass, Diastolic Function, Eccentric Hypertrophy
1. Introduction
Cancer treatment actually is a combination of surgery
associated to chemotherapy [1] and radiotherapy [2] to
prolong life duration and quality. Unfortunately this
combination can cause cardiotoxicity, it can precociously
on set but also arise after many years from therapy inter-
ruption [3] Many different chemotherapeutic agents can
determine cardiovascular complications such as heart
failure for left ventricular function impairment, all kinds
of coronary artery diseases and, at a lower rate, throm-
boembolism, and arrhythmias [4]. The same happens for
radiotherapy because of mediastinal irradiation [5]. It is
important to early recognize cardiotoxicity onset because
of its significant impact on the cardiac function and sur-
vival of cancer patients. To assess LV function, a base-
line evaluation of LV ejection fraction (EF) is always
obtained, before chemo and/or radio therapy start, and it
is recommended that the same methodology be used for
serial assessment [6] It was first established in clinical
practice since 1979 [7], based on their experiences, algo-
rithms have been developed for serial monitoring of
LVEF during chemiotherapy [8,9]. Measuring systolic
function through evaluation of the LVEF with echocar-
diography is one of the most commonly used measure-
ments in monitoring and diagnosing chemotherapy- in-
duced cardiomyopathy; however, it is not sensitive for
early detection of pre-clinical cardiac disease (subclini-
cal), and it is influenced by contractility and pre-load
/afterload effects leading to transient changes. Therefore,
other measurements of LV function (e.g., E/A ratio) have
been used to detect early cardiotoxicity in addition to

Early Diagnosis of Cardiac Toxicity Related to Antineoplastic Treatment
162
LVEF [10]. Due to an increasing aging population of
patients with cancer and the introduction of many new
cancer therapies, breast cancer often occurs on women
just affected by hypertension and/or diabetes [11] All
these conditions may affect left ventricular (LV) geome-
try, mass and diastolic function, but in what proportion it
is unknown. Early detection of these conditions may
contribute to improve heart failure prevention. The pur-
pose of our study was to determine the prevalence of left
ventricular changes of geometry, mass and diastolic dys-
function on a population of women affected by breast
cancer, submitted to radiotherapy and chemotherapy,
who present preserved LVEF.
2. Patients and Methods
We screened by our heart station 134 consecutive women,
all submitted to radiotherapy and/or chemotherapy, be-
cause of breast cancer, with a mean age of 52 ± 7 years,
affected by breast cancer and a group of 80 consecutive
women unaffected by breast cancer, hypertension and
diabetes, mentioned as control group, population’s char-
acteristics are reported on Table 1. During last three
years they underwent to conventional transthoracic
echocardiography (TTE), it was performed by GE Vivid
3 Expert echocardiography, an echo-Doppler system
equipped with a multifrequency transducer. Exclusion
criteria were diagnosis of: LV ejection fraction < 50%,
wall motion abnormalities, severe valvular disease, atrial
fibrillation and pulmonary hypertension, estimated from
the tricuspid regurgitation velocity by modified Bernoulli
equation. All patients were examined in a partially supine
position, with the head of the examining table elevated
by 30°. Recording followed a standardized protocol, the
parasternal acoustic window was used to record at least
10 consecutive beats, in two-dimensional and M-mode
recordings, to measure the LV internal diameter and wall
thicknesses, at or just below the tips of the anterior mitral
valve leaflets in both the long- and short-axis views. The
apical acoustic window was used to record at least 10
Table 1. Characteristics of enrolled women.
Women screened: 214
Women enrolled with breast cancer: 134
Women control group: 80
Left ventricular ejection fraction > 50%: 214 (100%)
Mean age women with breast cancer: 52 ± 7 years
Mean age women of control group: 52 ± 2 years
Height: 160 ± 10 cm.
Weight 68 ± 19 kg.
Body surface area (BSA): 1.58 ± 0.5 m2
Diastolic dysfunction (DD): 52 (38.8%)
Left ventricular hypertrophy (LVH): 38 (28.4%)
Both DD and LVH: 4 (2.9%)
Hypertensive women: 31 (23.1%)
Diabetic women: 23 (17.2%)
Diabetic and hypertensive women 8 (6%)
cycles of two- and four-chamber images to assess LV
wall motion. Pulsed Doppler sample volumes were
placed at the center of the mitral annulus in the four-
chamber view to record diastolic transmitral blood flow.
The Doppler beam was aligned to produce the narrowest
possible angle between the beam and the blood flow
vector. Pulsed-wave (PW) Doppler was performed in the
apical 4-chamber view to obtain mitral inflow velocities
to assess LV filling [12]. Continuous Wave (CW) Dop-
pler to assess peak E (early diastolic) and A (late dia-
stolic) velocities. On mitral inflow we measured peak
early filling (E-wave) and late diastolic filling (A-wave)
velocities, E/A ratio, deceleration time (DT) of early fill-
ing velocity, and isovolumic relaxation time (IVRT) [13].
PW DTI is performed in apical views to acquire mitral
annular velocities, sample volume was positioned at or 1
cm within the septal and lateral insertion sites of the mi-
tral leaflets. To measure systolic and early (E′) and late
(A′) diastolic velocities. For the assessment of global LV
diastolic function, we acquired and measured tissue
Doppler signals at the septal and lateral sides of the mi-
tral annulus and their average. E′ was used to correct for
the effect of LV relaxation on mitral E velocity, and the
E/E′ ratio was applied for the prediction of LV filling
pressures. On all patients E/E′ ratio was calculated. An
average ratio ≤ 8 identified patients with normal LV fill-
ing pressures, whereas a ratio ≥ 13 indicates an increase
in LV filling pressures. 86 When the ratio is between 9
and 13, a change in E/A ratio with the Valsalva maneu-
ver of ≥ 0.5 and maximal LA volume ≥ 34 mL/m2 were
indicative of increased LV filling pressures other meas-
urements are essential. The grading scheme was mild or
grade I (impaired relaxation pattern: mitral E/A ratio, <
0.8, DT > 200 ms, IVRT ≥ 100 ms, annular E′ < 8 cm/s,
E/E′ ratio < 8), moderate or grade II (PNF: mitral E/A
ratio 0.8 - 1.5, E/E′ ratio 9 to 12, and E < 8 cm/s), and
severe (restrictive filling) or grade III (E/A ratio ≥ 2, DT
< 160 ms, IVRT ≤ 60 ms, systolic filling fraction ≤ 40%,
E/E′ ratio > 13 [14]. Adequate measurements of diastolic
function were obtained in all patients. Hypertension and
or diabetic status was assessed after at least 6 months of
antihypertensive or antidiabetic therapy. LV mass was
estimated by M-mode echocardiography. Patients with
segmental LV dysfunction were excluded. LVMI was
derived by dividing LV mass by body surface area. LVH
was defined as LV mass index > 110 g/m2 for women
and > 134 g/m2 for men [12,15-17]. LVEF was deter-
mined on M-mode and checked on B-mode by Simp-
son’s rule. Left ventricular geometry was assessed on the
basis of relative wall thickness, classed as concentric
when ≥ 0.45 and as eccentric when ≤ 0.34 [18].
To determine intra- and inter-observer variability, each
of two investigators duplicated each measurement in 10

Early Diagnosis of Cardiac Toxicity Related to Antineoplastic Treatment163
randomly chosen patients to ensure that a correlation
coefficient of 0.9 or more was obtained by linear regres-
sion analysis. Measurements were made with a comput-
erized review station equipped with digitizing tablet and
monitor screen overlay. LV internal dimension and wall
thicknesses were measured at end diastole and end sys-
tole according to the American Society of Echocardi-
ography recommendations [19,20]. When optimal orien-
tation of imaging views could not be obtained, as is
common in subjects who are overweight, correctly ori-
ented linear dimension measurements were made with
two-dimensional imaging by the leading-edge technique
recognized by the American Society of Echocardiogra-
phy [21,22]. Doppler transaortic flow was performed in
the view in which peak flow velocity was maximal by
tracing the black-white interface of the Doppler flow
envelope after calibration for velocity and time [23,24].
2.1. Calculation of Derived Variables
End-diastolic LV dimensions were used to calculate LV
mass by an anatomically validated formula [12,15-17].
LV relative wall thickness (RWT) was calculated by for-
mula as: left ventricle RWT = IVS+PW/LVEDD, where
IVS is interventricular septum thickness, PW is posterior
wall thickness and LVEDD is LV end diastolic diameter.
f left ventricular RWT was greater than 0.45; it was clas-
sified as concentric geometry of LV and if less than 0.34;
classified as eccentric geometry [25].
2.2. Statistical Analysis
The relationships between concentric lv hypertrophy (lvh)
patients and eccentric lvh patients for all the above-men-
tioned echo findings were assessed by the chi-square test
for non-parametric analysis and student’s t-test for para-
metric analysis. A p value < 0.05 was considered signifi-
cant. Multivariate analysis was performed.
3. Results
All patients were enrolled during a period of 3 years, 54
of 134 women (40.2%), were affected by hypertension
and/or diabetes too, 8 of them by both, these women had
been on anti-hypertensive and or anti-diabetic medication
for almost 6 months prior to enrolment. No relation has
been found between medications used and outcome, pos-
sibly because of a high frequency of combination therapy
or serial monotherapy with different drugs.. The mean
age of all patients was 52.7 years, 53.7 on patients without
diabetes or hypertension, mentioned as free group (FG),
51.6 on women with almost one of two conditions, prone
group (PG) and 52.2 on control group (CG). We diag-
nosed LV hypertrophy on 10 women of FG (12.5%), 24
of PG (44.4%), p < 0.02 and 2 of CG (2.5%), p < 0.007
vs FG and p < 0.01 vs CG. According to LV geometry,
LV eccentric hypertrophy was present on 8 women of FG
(10%), 18 of PG (33,4%), p < 0.01 and 2 of CG (2.5%), p
< 0.006 vs FG and p < 0.01 vs CG; LV concentric hyper-
trophy was present on 2 women of FG (2.5%), 6 of PG
(11.1%), p < 0.05 and none of CG; LV concentric re-
modeling, (i.e. concentric geometry without LVH), was
present on 1 women of FG (1.2%), 3 of PG (5.5%), p <
0.003 and none of CG, Figure 1. LV diastolic dysfunc-
tion as filling impairment was on 20 women of FG (25%),
on 30 of PG (55.5%), p < 0.04 and on 2 of CG (3.7%), p
< 0.04 vs PG and p < 0.05 vs FG, diastolic dysfunction
was considered mild in all case and in no case LV filling
pressure were increased. 1 woman of FG and 3 of PG
were affected by LVCH and LV diastolic dysfunction)
DD, but this number of patients is too little to be reliable
for any evaluation. Coronary artery disease, without re-
gional wall motion abnormalities was diagnosed on 2
patients affected by diabetes and hypertension. The
women of all 3 groups were not statistically different in
terms of age and prevalence of smoking.
4. Discussion
The main outcome of our study is that patients treated by
chemotherapy and radiotherapy, present many different
changes of LV mass, geometry and function, in absence
of other risk factors for these changes. LV mass is in-
creased, LV geometry became often eccentric and some-
times concentric, LV filling is impaired also if they are
asymptomatic and despite a preserved LV ejection frac-
tion. For all these modification there is a statistical sig-
nificant different rate between our patients and general
population. The most frequent pattern is LV diastolic
dysfunction, followed by LV eccentric hypertrophy, at a
lower rate. This suggests that on these patients cancer
treatment may early impair LV diastolic filling and/or
may cause LV dilation, determining LV eccentric hyper-
trophy, while they are asymptomatic for cardiac disease.
Figure 1. Prevalence of left ventricular eccentric or concen-
tric hypertrophy and diastolic dysf unction on ou r popu lation.

Early Diagnosis of Cardiac Toxicity Related to Antineoplastic Treatment
164
LV filling pressure was normal in all patients, but we
have to consider that we are looking for early cardiac
dysfunction. We know that a combined systo-diastolics
dysfunction is relatively common during on women who
underwent to cancer therapy [26-28], so it is reasonable
to perform serial evaluation of LVEF [6], as prescribed
by current guidelines, but when LVEF became impaired,
it occurs a rapid development of severe heart failure.
Early diagnosis of LV diastolic dysfunction and/or LV
eccentric hypertrophy can be achieved by a simple tool
such M-B mode echocardiogram, associated to PW and
TDI Doppler, and it is more sensitive than LVEF in the
early detection of LV unfavourable changes in geometry,
as assessed by LV relative wall thickness and function.
LV geometry eccentric pattern is common among our
patients, not the same for concentric pattern, so we can
suppose that cancer therapy doesn’t determine changes
on peripheral resistances, but directly affect myocardial
cells, the same explanation can be accounted for LV dia-
stolic dysfunction not due to increased peripheral resis-
tances but to direct myocardial cell damage. The bio-
logical mechanisms underlying cancer therapy-associated
cardiac dysfunction remain to be fully elucidated, but
generation of reactive oxygen species (ROS) and induc-
tion of cardiac myocyte apoptosis are hypothesized to
play a central role. Concerning, chemotherapy ROS may
continue to be produced by a drug retained within myo-
cytes contributing to late-occurring cardiovascular injury
[29]. Also about radiotherapy, the generation of ROS is
thought to play a major role [30]. Another important out-
come is that all above mentioned changes in LV mass,
geometry and function are present at a statistical signifi-
cant different higher rate among a population of women
treated by chemotherapy and radiotherapy, but just af-
fected by cardiovascular risk factors as diabetes and or
hypertension [31], compared with our population of
women treated for cancer but free from diabetes and or
hypertension. So that the cardiac unfavorable changes,
due to cancer therapy, add up to those due to diabetes
and or hypertension, increasing their cardiovascular risk
of events [31,32]. All these patients need of a careful
monitoring of heart condition to prevent heart failure and
other cardiac events. The main limitation of our study is
the limited number of patients enrolled, so we cannot
individuate subgroups according to different treatments,
not even we can differentiate diabetic from hypertensive
women, otherwise it is one of the first studies concerning
breast cancer patient treated by both chemotherapy and
radiotherapy, with preserved LV ejection fraction.
5. Conclusions
An abnormal diastolic function is more common among
women affected by breast cancer and treated for it than in
general population, the same happens for LV eccentric
hypertrophy but at a lower rate. 40% of women were
affected by hypertension, diabetes or both, and they have
a higher rate of LV eccentric hypertrophy and diastolic
dysfunction than women treated for cancer but unaf-
fected. We know that patients affected by these LV
changes had worse event-free survival than patients with
normal LV mass, geometry and function. LV eccentric
hypertrophy and diastolic dysfunction are predictors of
heart failure on asympomatic women. Screening with
Doppler echo techniques may be helpful in identifying
patients at high risk for subsequent cardiac events.
6. Disclosures
All authors have no financial disclosures, they report no
biomedical financial interests or potential conflicts of
interest.
7. Acknowledgements
The authors thank the nurses Grazia Quaranta, Emmia
Donativo and Anna Paola Gennaro, for the support to the
survey of the clinical data.
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