Background Anthracycline-induced cardiotoxicity can reach an irreversible phase; therefore great efforts are made to diagnose it early. As the right ventricle (RV) is smaller than the left, the right side of the heart is probably influenced by anthracycline to a greater extent and in a shorter time. The purpose of the present study was to investigate the early effects of chemotherapy on the right side of the heart.
Methods This cross-sectional study was performed in Isfahan University hospitals from August 2014 to December 2015. Subjects were 67 patients with breast cancer who were planned to receive anthracycline for the first time. Echocardiography was performed before administration of anthracycline and 6 months later. Variables included right heart measures (RV end-diastolic dimensions, right atrium length and diameter), RV fractional area change (RVFAC), index of myocardial performance (Tei index), tricuspid annular plane systolic excursion (TAPSE), pulmonary artery systolic pressure, lateral tricuspid annular early and late diastolic velocities, and tissue Doppler diastolic and systolic velocities.
Results Forty-nine of the subjects completed the study. RV end-diastolic diameters and Tei index (0.31 to 0.37) were significantly increased (p<0.001). RVFAC (49.83% to 43.59%) and TAPSE (18.8 to 17.7 mm) were significantly decreased (p<0.001). There was a significant reduction in E (57.06 to 46.59 cm/s, p<0.001), E/A ratio (1.42 to 1.18, p<0.001), E′ (16.73 to 12.4 cm/s, p<0.001), E′/A′ ratio (1.21 to 0.9, p<0.001) and S′ (12.59 to 10.57 cm/s, p<0.001). Systolic pulmonary arterial pressure (20.63 to 22.24 mm Hg, p=0.04) was significantly increased.
Conclusions This study shows a significant decrease in RV systolic and diastolic function during chemotherapy for 6 months. These reductions are in the normal range and can probably be considered an early indicator of anthracycline-induced cardiotoxicity.
- Right ventricle function
- Tissue Doppler echocardiography
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With the great advances in screening and treatment strategies for breast cancer, survival of this disease has steadily increased over the last three decades. The overall 5-year survival rate has improved from 63% in the 1960s to 90% in 2012.1 Anthracyclines are among the most used and effective antineoplastic agents, especially in breast cancer. Like other antineoplastic drugs, anthracyclines have some side effects, among which cardiotoxicity has the potential for substantial morbidity and mortality in a growing number of patients. Anthracycline-induced cardiotoxicity can present as a decline in cardiac function that can be symptomatic or asymptomatic and in most cases begins as diastolic dysfunction and progresses to systolic dysfunction.2
Available data suggest that about one-third (27%) of adult patients exposed to anthracyclines will show cardiac dysfunction over the 5 years after treatment, mostly beginning in the first year, with 2–5% developing overt heart failure which causes a reduction in the survival rate to 50% at 1 year.3–7
Various predisposing factors have been proposed, such as total dose of anthracycline >550 mg/m2, high rate of administration, previous chest irradiation, advanced age, female sex, and coexistent heart disease and/or arterial hypertension.4 ,8–10
Chemotherapy-induced cardiotoxicity includes cardiomyopathy with or without congestive heart failure symptoms mostly defined as left ventricular ejection fraction (LVEF) below 55%.4 These manifestations may be irreversible at the time of diagnosis of cardiomyopathy, so great efforts are made to diagnose heart damage as soon as possible.
Whereas left ventricular (LV) function after chemotherapy has been studied several times, there are few studies evaluating right ventricle (RV) function. The mortality rate in the presence of RV and LV failure increases, and RV function is an important prognostic factor of heart failure.10 ,11
There are similarities in the blood supply and cell structure of the ventricles. However, because the RV has a smaller mass and fewer myocytes than the LV, anthracyclines should, theoretically, have a more pronounced effect on the RV. RV indices can also be the first echocardiographic signs of anthracycline-induced cardiomyopathy.
While biopsy is the gold standard method for diagnosis, there are various diagnostic methods for subclinical cardiac toxicity (eg, functional tests, biomarkers, MRI, isotope imaging). Echocardiography is a non-invasive, cost-effective and widely available cardiac imaging tool that is well positioned to serve as the primary screening modality for chemotherapy-induced cardiotoxicity, and tissue Doppler echocardiography (TDE) indices have been shown to be sensitive for detecting local damage to ventricles before the heart is globally affected.12 ,13
Therefore, this study was designed to evaluate changes in echocardiographic variables of the RV in patients with breast cancer treated with anthracycline who are asymptomatic.
Methods and materials
Participants and target group
This cross-sectional study was conducted in the cardiology department of Isfahan University of Medical Sciences hospitals, including Alzahra, Noor and Chamran hospitals, during August 2014 to December 2015. The echocardiographic indices of patients who had received anthracycline treatment were analysed. Women <50 years old diagnosed with breast cancer before treatment with anthracycline for the first time were included. Patients older than 50 years (because diastolic function may begin to decrease at this age), patients with diabetes mellitus, hypertension, non-sinus rhythms, renal failure (serum creatinine >1.6 mg/dL), LVEF <55%, moderate and severe valve regurgitation, documented coronary artery disease and liver failure (a threefold increase in liver enzymes) and patients receiving an unusual dose of anthracyclines were excluded from the study.
The study flow chart is depicted in figure 1. The study subjects were 67 patients with breast cancer, who had been diagnosed by an oncologist. Physical examination and echocardiography were performed before administration of anthracyclines for the first time and 6 months later. The study received ethics approval from the ethics committee of Isfahan University of Medical Sciences (394415), and written informed consent was obtained from all participants. Echocardiographic variables were measured before administration of anthracyclines and 6 months after the first dose.
All echocardiographic examinations were performed by the same cardiologist and reviewed by an echocardiologist, and, in the case of discrepancy, a third cardiologist blinded to this study was asked to review. After a thorough physical examination, patients underwent transthoracic echocardiography (Vivid 3; GE Medical Systems, Horten, Norway) in the left lateral decubitus position, and LVEF was measured by a modified biplane Simpson method. RV diameters in the four-chamber apical view were also measured. Parasternal, apical and subcostal views were used for assessment of RV systolic function. Systolic pulmonary artery pressure was calculated by adding the tricuspid regurgitation pressure to the right atrial pressure as estimated from the inferior vena cava diameter and collapsibility.
Standard features of echocardiography including parasternal (long/short axis), apical (two/four chamber) and subxiphoid (long axis) were recorded in all patients. The area of RV in systolic and diastolic phase was measured in apical view (four chamber) to calculate RV fractional area change.
Myocardial systolic and diastolic (early/late) velocities were measured in apical four-chamber view by sample volume at the junction of the tricuspid valve cusp and RV free wall.
Tricuspid annular plane systolic excursion (TAPSE) is the usual method for evaluating the performance of the RV through the tricuspid valve annulus measured by M-mode imaging on apical four-chamber view.
Analysis was performed using descriptive statistics such as mean (SD) and analytical statistics such as paired t test, χ2 tests by SPSS V.22. A p value <0.05 was considered significant.
As shown in figure 1, after exclusion of patients receiving unusual doses of anthracycline, patients with reduced left heart function during chemotherapy, and patients with complications affecting the right heart (pulmonary thromboembolism), 49 patients were analysed. Table 1 shows the basal characteristics of the patients: mean±SD age 40.75±7.14 years; 67% of patients (37/49) had breast surgery in 21±6 days before chemotherapy; and the number of chemotherapy courses in patients was 6.57±0.91. All patients received about 450–550 mg/m2 anthracycline.
Table 2 shows echocardiographic results for the LV: the mean EF was 59.08±3.37% before chemotherapy and 58.8±2.78% 6 months later; there were no significant changes in LV variables.
Table 3 shows echocardiographic results for the RV. RV end-diastolic diameter in the base, mid and apex were increased during anthracycline treatment (2.32 to 2.44 cm, 3.008 to 3.08 cm, 7.35 to 7.46 cm, respectively; p<0.001). RV fractional area change (RVFAC) was decreased (49.83% to 43.59%; p<0.001).
No significant changes in right atrium variables such as length and diameter (p=0.119 and 0.111, respectively) were observed. We also found no significant changes in late diastolic velocity (A), A′ and E/E′ ratio. A significant reduction was observed in TAPSE (18.8 to 17.7 mm, p<0.001), E (57.06 to 46.59 cm/s, p<0.001), E/A ratio (1.42 to 1.18, p<0.001), E′ (16.73 to 12.4 cm/s, p<0.001), E′/A′ ratio (1.21 to 0.9, p<0.001) and peak systolic velocity (S′) (12.59 to 10.57 cm/s, p<0.001). Systolic pulmonary arterial pressure increased significantly (20.63 to 22.24 mm Hg, p=0.04) in the 6 months after administration of the first dose of anthracycline.
In this study we are trying to understand the effect of anthracycline on echocardiographic base indices. RV anthracycline-induced cardiotoxicity has not been studied comprehensively; in numerous studies involving anthracyclines in most of them, subclinical cardiac damage was demonstrated.11 Diastolic impairment in the LV was shown to precede systolic derangement.14–16 Currently, RV dysfunction is not considered for diagnosis of cardiotoxicity and its incidence and prognostic value in patients receiving anthracyclines are unknown. However, owing to thinner walls and fewer myofibrils in the RV than in the LV, the RV may be more susceptible to damage, as has been shown in this study. The limited literature on the impact of anthracycline on the RV may reflect the absence of robust techniques for assessing RV function.
The effect of chemotherapy on the RV was first demonstrated in a study on 41 doxorubicin-treated patients with various cancers, in whom RV wall motion abnormalities were more common than LV abnormalities on radionuclide ventriculography.17 More recently, a cardiac MRI study of patients receiving anthracyclines with or without trastuzumab illustrated RV dysfunction in 34% of the patients by 12 months, while LV dysfunction was seen in 26%.18 Interestingly, RV dysfunction occurred as early as 4 months after therapy and represented an early sign of myocardial injury. Another echocardiography study identified a slight reduction in RVFAC and TAPSE even as early as the 3rd cycle of doxorubicin therapy in 37 anthracycline-treated patients with breast cancer,19 Our study also indicated significant reduction in RVFAC (49.83% to 43.59%) and TAPSE (18.8 to 17.7 mm) over 6 months of follow-up.
Belham et al20 reported that low-dose anthracycline was associated with an increase in the LV Tei index, whereas there was no significant change in the RV Tei index. As results from our study show, significant changes in the RV Tei index may be due to the longer follow-up period.21
Cottin et al22 evaluated cardiac function by radionuclide angiography in 33 women treated with anthracycline and found impairment in the systolic and diastolic LV radionuclide parameters without any alteration in right heart function. Yildirim et al23 investigated LV and RV function using dobutamine stress echocardiography and TDE in asymptomatic paediatric long-term survivors of different types of malignancy who had received anthracycline and detected that RV Sm′, Am′ and E′/A′ were impaired.
There were significant changes in systolic and diastolic variables within the normal range during the ongoing chemotherapy in our study. Our results are not consistent with the work of Cottin et al, which is probably due to the use of different methods of evaluation.
TDE revealed decreasing tricuspid annular velocities and marked changes were observed especially in tricuspid E′/A′ and E/A ratio. It has been reported in many studies that RV diastolic dysfunction precedes apparent systolic dysfunction. We have detected diastolic impairment in our population. LV TDE has been evaluated in many studies and shown to be an early indicator of cardiac damage,24–26 and, as shown in this study, RV TDE can be used for detecting cardiac damage.
Despite a reduction in RV systolic and diastolic function, all variables remained in the normal range provided by the guidelines of the American Society of Echocardiography for the echocardiographic assessment of the right heart.27 The reason for the variables remaining in the normal range as seen in some studies may be the relatively short follow-up period compared with previous studies.
We detected a slightly significant increase in systolic pulmonary artery pressure within the normal range. Because of the intact LVEF, this increase could not be explained by LV dysfunction and we think it is mostly due to reduced RV function other than impairment in pulmonary resistance. However, it should be kept in mind that chemotherapeutic agents are among the possible causes of idiopathic pulmonary arterial hypertension by increasing pulmonary vascular resistance, although this is not common.28
The limitations of this study are the lack of comparison of LV and RV variables and the short follow-up period. We recommend that studies be carried out with more frequent echocardiography evaluations to identify the earliest abnormal variable.
We have demonstrated a significant decrease in RV echocardiographic indices in the normal range during chemotherapy with anthracycline over a relatively short period of time, which is probably an early indicator of anthracycline-induced cardiotoxicity. Interestingly feasible for routine use, TDE indices (which are less load dependent) were impaired and all changes happened while patients were symptom free. This investigation may prompt attention to the right heart in patients treated with anthracyclines and may lead to larger trials which also test the possible association of short-term changes in right heart echocardiographic indices and anthracycline-induced cardiomyopathy and their prognostic value.
Right ventricular anthracycline-induced cardiotoxicity has not been studied comprehensively.
Right ventricle systolic and diastolic function decreases significantly during breast cancer chemotherapy with anthracyclines.
Right ventricular echocardiographic indices can be considered as early indicators of anthracycline-induced cardiotoxicity.
Current research questions
What are the long-term effects of anthracycline on the right ventricle?
Is there any sensitive and specific echocardiographic marker for detecting anthracycline-induced cardiotoxicity before irreversible damage occurs?
What is the first echocardiographic variable to change during chemotherapy with anthracyclines?
This study was carried out as a cardiology course residency thesis. We gratefully acknowledge the dedicated efforts of the investigators, the coordinators and the volunteer patients who participated in this study.
Contributors Conception and design of study: MAE, FM and MK. Acquisition of data: MAE and MK. Analysis and/or interpretation of data: MAE, FM and MK. Drafting the manuscript: MAE, FM and MK. Revising the manuscript critically for important intellectual content: MAE, FM and MK. Approval of the version of the manuscript to be published: MAE, FM and MK.
Funding This work was supported by Isfahan University of Medical Sciences, Isfahan, Iran (grant number: 8/7832).
Competing interests None declared.
Patient consent Obtained.
Ethics approval Ethics committee of Isfahan University of Medical Sciences.
Provenance and peer review Not commissioned; externally peer reviewed.