DISCUSSION
In our study of 96 long-term survivors with diffuse large B-cell
lymphoma treated with anthracyclines, we examined the role of left and
right ventricular parameters before the start of anthracycline and after
the completion chemotherapy in identifying the late occurrence of CAEs
(cardiac death, symptomatic heart failure, arrhythmia, Subclinical
Cardiac dysfunction). Although LVGLS had proven prognostic value, RVEF
provided additional and independent information and added incremental
value to a model including LVGLS. We found that by using a model
combined LVGLS and RVEF could increase the sensitivity for predicting
the late CAE. To our knowledge, this is the first study to evaluate the
role of combining RV and LV function among patients with lymphoma for
predicting late CAE in the context of R-CHOP regimen. Previous published
studies mainly focused on the role of LVGLS in cardiovascular
toxicity[20-22]. This study has the following novel findings: 1). We
reported the proportion of patients with CAE caused by R-CHOP treatment;
2). We applied simultaneous 3-D LV and 3-D RV assessment 3). RVEF
decreased during the chemotherapy was a strong predictor of CAE, and 4)
combining LVGLS and RVEF may increase the sensitivity for estimating
cardiovascular prognosis after chemotherapy.
The majority of CAE reported in our cohort were arrhythmia (8) including
and heart failure (5) with an occurrence of 8.3% and 5.2%,
respectively within a median of 6 years of follow-up. The pooled
proportion of patients developing heart failure (5.2%) in our study is
in line with previous studies reporting on the development of
symptomatic heart failure, with a 4-5% incidence at a cumulative
doxorubicin dose of 400mg/m2[23, 24]. In our
study, patients received concomitant treatment with cyclophosphamide,
which complicated the interpretation of the association of doxorubicin
and left ventricular dysfunction. A study that explored the association
between cyclophosphamide doses and left ventricular dysfunction, found
patients whose doses greater than 1.55 g/m2 were
associated with a low incidence of cardiotoxicity[25]. Little is
known about right ventricular (RV) function in patients with lymphoma
treated with R-CHOP, a small sample study found survivors had markedly
increased risk (26%) of having impaired RV function (based on ejection
fraction, and compared with normative values) [13]. The proportion
of patients with impaired RV function (13%) in our data is quite high,
and in many conditions, impaired RV function is associated with an
increased risk of heart failure.
LVEF was one of the most important parameters for the assessment of
cardiac function and for predicting CAE. However, many studies have
proved that LVEF remained stable and within normal limits during the
whole course of chemotherapy[20, 26, 27]. Anthracycline-induced
cardiomyopathy can be a regional or diffuse pattern so the global LV
function could remain normal by compensatory mechanism of healthy
cardiomyocyte in the early stage[28]. Similarly, LVEF was not chosen
in stepwise Cox proportional hazard analysis in our study. GLS is a
sensitive measure of cardiac function and cardiac injury. Many studies
have proved that patients with a reduction in GLS despite a preserved EF
are at risk for cardiac injury and cardiac dysfunction [29, 30]. A
previous study found GLS was associated with cardiac events while LVEF
was within the normal range in patients treated with anthracyclines. In
our data, LVGLS was also associated with the late CAE, and the threshold
of GLS allowed us to identify patients who developed CAE with 66.7%
sensitivity and 82.1% specificity. The use of GLS may allow the
identification of a group of patients at risk of subsequent CAE and help
to guide preventive medicine.
The assessment of RV function has become increasingly popular and been
recognized as important to predict cardiac toxicity [31]. RV
functional assessment with 2-dimensional and Doppler echocardiography
has shortcomings due to the complex geometry of the right ventricle.
Nagata et al validated the accuracy of RV volumes and RVEF measurements
by 3D TTE against CMR. Although the manual editing of RV endocardial
surface was required by 3D TTE, the 3D TTE was more widely adopted and
convenient compared with CMR measurements. RV function by 3D TTE has
emerging roles in future prognosis on chemotherapy patients [15].
RVEF<40% was a significant independent predictor of mortality
after adjustments for age and LVEF. Gulati et al found that RVEF
<45% was a powerful predictor of adverse cardiac events
[32]. Some studies focused on the consistent impairment of RV
function among in survivors of childhood cancer after reaching
adulthood[33, 34]. In the current study, we determined the
prognostic value of 3D RVEF in R-CHOP treated patients without severe
cardiac disease. We demonstrated that 3D RVEF is significantly
associated with late CAE. Using variables selected by a stepwise forward
procedure in Cox proportional hazard analysis, we established an
incremental value of 3DRVEF over the LVGLS for predicting CAE. Our
results clearly showed that 3DRVEF is an independent predictor of CAE.
Current guidelines on follow-up after chemotherapy focus on left
ventricular function[9]. Many studies have started to explore and
validate the important role of impaired RV function in prognosis in a
wide range of diseases[10, 11, 35]. We feel that impaired RV
function is a strong predictor of CAE in cancer survivors and a
combination of LV and RV function parameters during chemotherapy can
facilitate the prevention and treatment.
Finally, we want to emphasize the importance of the 3-D echo image
quality for the meaningful analysis of the cardiovascular adverse event.