Early Diagnosis of Cardiac Toxicity Related to Antineoplastic Treatment

doi:10.4236/jct.2011.22019

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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.

Email: [email protected]

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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