Anthracyclines are considered the most predominant cardiotoxic drug that generates reactive oxygen species which negatively affect cardiac tissues leading to HF. [20] In fact, in one meta-analysis, anthracycline therapy revealed a greater risk of clinical and subclinical cardiotoxicity compared with non-anthracycline-containing regimens. [21] Despite the unfortunate negative consequences of anthracycline chemotherapy, it plays a key role in treating various types of cancers including 32% of breast cancer, 57–70% of geriatric lymphoma, and 50–60% of childhood cancer. [22]
In this study, anthracyclines were assessed on 66 female patients with breast cancer regarding their effect on LV function. 18 patients developed cardiotoxicity had a significant deterioration in LVGLS early before the reduction in LVEF, Clinical and subclinical anthracycline-related LV dysfunction had been well-researched in breast cancer patients. [23, 24]
However, RV dysfunction was not counted in the diagnosis of cardiotoxicity. The anthracycline–related toxic effects on the RV have become the focus of extreme interest, as the prognostic significance of RV dysfunction on the outcome of patients with HF was established. [25, 26] The thinner structure of the RV with fewer myofibrils makes it susceptible to damage by chemotherapy, Although the evaluation of the RV by conventional 2DE has a restricted accuracy. The CMR is considered to be the gold standard technique for the assessment of RV volume and function, recent studies have confirmed the accuracy of 3DE-determined RV volumes and function. STE-derived RV longitudinal strain has been shown to be achievable, reproducible, and prognostic in oncological patients. [16, 17] Our study was designed to assess the changes in RV function and volumes after chemotherapy using 3DE and to detect subclinical RV dysfunction using 2D-STE.
In the current study, the conventional RV echocardiographic parameters showed a slight reduction in FAC measurement that appeared late during the follow-up by 6 months and this reduction increased to become significant at the end of 9 months after the chemotherapy. On the other hand, TAPSE did not show a significant reduction at the end of chemotherapy or through follow-ups. Similar studies reported a significant reduction in RV FAC during the period of chemotherapy and follow-up even though, the reduction was within the normal range.[27, 28] Other studies reported a significant change in TAPSE at the end of chemotherapy or during follow-up.[29, 30] Rui et al.[31]and Cherate et al.[32] couldn't detect a change in FAC or TAPSE in consort with subclinical RV deterioration at the end of chemotherapy even though, Tanindi et al.[33] and Xu et al. [34] showed a significant change in both at the end of chemotherapy and after chemotherapy by 12 months respectively. Therefore, the controversy in evaluating RV function by traditional methods leads to diminishing their role in early subclinical RV affection, which is owing to the complex geometry of RV.
The RVESV and RVEDV in the cardiotoxic group of our study increased statistically after the end of chemotherapy by 6 months and continued by 9 months, however, the increase in ESV was more significant than in EDV at 6 months from the end of chemotherapy (P = 0.005 vs P = 0.021 respectively). RVEF decreased concomitantly with LVEF, and they started during the follow-up and reduced significantly after 9 months, 10 patients (15.1% of total patients) had a significant RV dysfunction (RVEF < 45%). The reduction in RVEF wasn't accompanied by an increase in PASP (afterload), and this could be supported by the direct toxic effect of anthracycline on RV as well as LV. In similar, Rui et al. [31] studied the anthracycline effect on 74 patients and showed a significant increase in RVESV and RVEDV during the chemotherapy, followed by a reduction in RVEF at the end of chemotherapy. Moreover, Wang et al. [30] reported a significant increase in RV volumes accompanied by an earlier decrease in RVEF at the end of chemotherapy and subsequently the reduction in LVEF later during the follow-up in 61 patients with B-cell lymphoma. In agreement with our results, Souza et al. [35] and Grover et al. [36] studied anthracycline impact on RV using CMR in patients with breast cancer and demonstrated right ventricular remodeling induced by anthracycline in the form of myocardial oedema, decrease in RV mass, and myocardial fibrosis with an increase in volumes mainly ESV followed by a decrease in RV function.
Our study reported in the cardiotoxic group, RV dysfunction was detected in 10 patients (55%) by RVEF, concomitantly with the reduction in LVEF, and detected in 16 patients (88%) by RV FWLS early after 6 months of therapy, both RV FWLS and RVGLS reduced significantly after 6 months and continued to decrease after 9 months (p = 0.001) compared to baseline values. RV dysfunction evaluated by conventional parameters TAPSE and S` had no significant changes
In the same line with Vahabi et al. [37] who studied 62 patients to assess the decline in RV GLS, FAC as well as RV FWLS following anthracyclines treatment. The study revealed a significant reduction in the RV FWLS and GLS in patients who developed cardiotoxicity compared with patients with preserved LVEF, and no statistically significant change was observed in the conventional 2D measures of RV function. Similarly, Planek et al. investigated the cardiotoxicity of doxorubicin in 35 lymphoma patients and demonstrated a significant deterioration in RV FAC, RV FWLS as well as RV GLS after a 6-month follow-up. Unlike ours, their study did not detect any significant reduction in LVEF after six months of follow-up and concluded that doxorubicin therapy is associated with subclinical RV dysfunction. [28] The study of Xu et al. [34] who assessed RV function in 95 women with breast cancer receiving epirubicin therapy, found that 3D GLS of LV and both RV GLS and FWLS were depressed significantly at 12 months without the occurrence of cardiotoxic affection of LVEF and RVEF, these variations of 3DRV strain allow the identification of subclinical RV dysfunction when conventional parameters unaffected, same as our results.
Initially, anthracycline-associated cardiotoxicity was linked to some factors including high cumulative doses and patients with a history of cardiovascular diseases. It was revealed that a dose of > 400 mg/m2 was associated with the highest risk of cardiac injury with an early incidence of HF approximating 3%, 7% at a dose of 550 mg/m2, and 18% at 700 mg/m2. Consequently, it was suggested that a maximum lifetime cumulative dose of anthracycline should not exceed 550 mg/m2. [38] Then it was settled to limit the cumulative anthracycline dose to 400 to 450 mg/m2. [39] According to our study results, the patients received chemotherapy in the form of four cycles of anthracycline followed by 12 weeks of paclitaxel. The mean cumulative dose of anthracycline in the cardiotoxic group was (374.56 ± 36.66) while in the non-cardiotoxic group, it was (363.33 ± 36.75) with a non-significant difference. Furthermore, there was a significant negative association between the cumulative dose of anthracycline and the declining percentage in RV FWLS (r= -0.806; p < 0.001). On the contrary, various studies have reported cardiotoxic effect that is associated with lower anthracycline doses. In Cajella and colleagues' study [17], the former LVEF was associated with doxorubicin's mean dose of 231 ± 19 mg/m2. Similarly, Planek et al. [28] reported at a cumulative doxorubicin dose of more than 200 mg /m2 and found a significant deterioration in RV FAC, RV FWLS, and RV GLS. In fact, one study has exhibited 1.6 folds of getting HF at a dose of 300 mg/m2. [40]
There is no consensus in the literature regarding the RV GLS value that can expect cardiotoxicity, an essential argument in RV strain analysis is whether GLS or FWLS should be assessed. The ROC curve analysis for the changes in RVFWLS proved that a relative drop of RV FWLS > 19.3% had a sensitivity of 83% and a specificity of 71%, (AUC = 0.82) to identify patients who developed cardiotoxicity, RV FWLS had a higher predictive value than GLS for identification of cardiotoxicity. Keramida et al. [41] observed that the cut-off value of RV GLS percent change that identified cardiotoxicity was 14.8% with a sensitivity of 66.7%, a specificity of 70.8%, and the AUC of 0.68 in cancer breast patients receiving trastuzumab.
Cherata et al. [32] who assessed RV systolic function in 68 cancer patients receiving cardiotoxic agents demonstrated that a 17% reduction of RV FWLS had a sensitivity of 55% and a specificity of 70% with an AUC of 0.75 to identify patients with CTRCD
Another study reported that the optimal cut-off value of 17.5% of 3D RV FWLS percent changes showed high prognostic accuracy for subclinical cardiac dysfunction, with an AUC of 0.74, a sensitivity of 80.5%, and a specificity of 65.8%. [34]
Our study found that the longitudinal strain analysis permits early identification of subclinical RV dysfunction when the standard 2D indices of RV function are unaltered. RV FWLS is more accurate than RV GLS in the evaluation of RV systolic function since the intraventricular septum is a constituent part of the LV.