Autonomic and cardiac evaluation upon sub-therapeutic doxorubicin administration

Doxorubicin (DOX) is a chemotherapeutic agent that improves the survival and quality of life of patients with solid tumours. However, these improvements are counterbalanced by various dose-dependent side effects including cardiac dysfunction, which may occur in a subset of patients leading to treatment discontinuation. In addition, despite overall insufficiently studied, available data clearly show that women are more susceptible to drugs toxicity due to sex differences in drug metabolism or sensitivity. Regarding doxorubicin, apart its acute toxicity, women are also more vulnerable to late cardiotoxicity. Currently, there are no robust clinical imaging techniques or biomarkers available to detect DOX-cardiotoxicity before functional decline and, despite treatment personalization, subclinical signs of toxicity are not yet well identified. Thus, in the present work, we sought to characterize the toxic effects of a sub-therapeutic dose of doxorubicin upon cardiovascular and autonomic function. For that, adult healthy female wistar rats (n=14), aged >3 months, were intraperitoneally treated with doxorubicin (2 mg/kg) at weekly intervals for up to 4 weeks. A control (Ctrl, n=7) group received saline solution 0,9% NaCl as a vehicle. Rats underwent an echocardiographic evaluation at 4 weeks. Blood pressure, heart rate and respiratory frequency were assessed in an acute experiment. Cardiovascular variability studies in the time-frequency domain (LF, HF and LF/HF calculation) and cardiorespiratory reflexes assessment were performed. T-Student test for paired observations was applied (level significance p<0.05) DOX-treated animals showed a severe bradypnea and hypotension, significant decrease in ejection fraction and fractional shortening, sympatho-inhibition and reduced baroreceptor reflex gain and chemoreflex sensitivity. Our functional results might be due to cellular respiratory dysfunction and vascular adaptations induced by doxorubicin via TNF alpha actions at central nervous system (CNS) and peripheral level. In fact, peripheral TNF alpha release elicits NO production, which through vasodilation will induce hypotension and baroreceptor reflex adjustments. Reinforcing these actions, and despite doxorubicin low ability to pass BBB, TNF alpha acting at CNS induces neuronal apoptosis and impairment of mitochondrial function which might also contribute to affect autonomic and respiratory function, expressed by a decreased chemoreflex sensitivity and sympathetic tone. In conclusion, sub-therapeutic doses of doxorubicin are able to produce per se the impairment of autonomic and cardiac functions. Thus, a tight monitoring of these functions in patients treated with therapeutic doses of doxorubicin is highly recommended. FUNDunding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Fundação para a Ciência e a Tecnologia

Cardiovascular magnetic resonance for early detection of late cardiotoxicity in asymptomatic survivors of hodgkin and non-hodgkin lymphoma

Funding Acknowledgements Type of funding sources: None. Background Long-term survivors of Hodgkin (HL) and non-Hodgkin (NHL) lymphomas experience late adverse effects of mediastinal radiotherapy and/or anthracycline containing chemotherapy, which lead to premature cardiovascular morbidity and mortality. It is unknown whether early stages of myocardial dysfunction and heart failure in these survivors can be detected by cardiovascular magnetic resonance imaging (CMR). Purpose To identify early sensitive markers for the detection of subclinical late cardiotoxicity using CMR in asymptomatic survivors of HL and (primary mediastinal large B-cell lymphoma) NHL. Methods For this prospective observational study, we included 80 HL or selected NHL survivors, who have been free of disease for ≥5 years and were treated with mediastinal radiotherapy (RT) with/without chemotherapy. Patients with known cardiac disease were excluded. Included patients were compared to 40 age- and sex matched healthy controls. CMR included 1) cine imaging for assessment of left ventricular (LV) and right ventricular (RV) dimensions, systolic function and strain; 2) 2-dimensional late gadolinium enhancement (LGE) imaging; 3) T2 mapping and 4) pre- and post-contrast T1 mapping (MOLLI) for assessment of native T1 values and extracellular volume (ECV). Results Of the 80 patients, 78 (98%) had a history of HL and 2 (2%) of NHL with a mean age of 47 ± 11 years (46% male). All patients were treated with mediastinal RT which was combined with anthracycline containing chemotherapy in 68 (85%) patients. The median interval between diagnosis and CMR was 20 [14 – 26] years. Differences in CMR characteristics between patients and healthy controls are shown in the table. LV end-systolic volume was statistically significantly higher, but LV ejection fraction and mass were significantly lower in patients compared to healthy controls. RV volumes were significantly lower in patients, but RV ejection fraction was preserved. Strain parameters of the LV, i.e. global longitudinal strain, global circumferential strain and global radial strain, were slightly but significantly reduced in patients. No significant differences were found in myocardial T2 times and ECV; however, native myocardial T1 time was significantly higher in patients compared to healthy controls. LGE was detected in 25% of the patients and in the majority of patients with LGE this was classified as hinge point fibrosis. Conclusion Asymptomatic survivors of HL and NHL are not exempt of late cardiotoxicity, which can be detected by subtle changes in LV myocardial function, strain and native T1 value with CMR. Furthermore, late gadolinium enhancement was present in 25% of the patients. Further longitudinal studies are needed to assess the implication of these changes in relation to clinical outcome.

Pre-anthracycline left ventricular ejection fraction (LVEF) assessment and long-term cardiovascular (CV) outcomes in adolescent and young adult (AYA) lymphoma survivors.

e24060 Background: Anthracyclines are known to cause long-term cardiotoxicity. There are no specific guidelines for CV screening and follow-up of AYA patients treated with anthracyclines. Pediatric guidelines focus on long-term imaging surveillance, while for adults, LVEF assessment prior to anthracyclines is recommended. Multiple studies have demonstrated LVEF assessment rarely impacts treatment decisions, especially in the absence of CV symptoms/risk factors, adds to unnecessary costs and delays treatment initiation. Our study aimed to determine the pre-treatment LVEF assessment practices in AYA lymphoma patients treated with anthracyclines and its association with long-term cardiotoxicity. Methods: AYA survivors diagnosed with lymphoma > 5 years ago and treated with anthracyclines at age 15-39 years were identified in a retrospective single institution registry. To ensure adequate follow-up, at least 2 follow-up visits during 2015-19 were required. Data abstracted on eligible subjects included documentation of pre-treatment LVEF evaluation, clinical rationale and treatment regimen. CV risk factors and events were collected pre-treatment and during follow-up. Descriptive statistics were used to summarize data. Results: 64/115 (56%) of AYA lymphoma patients underwent pre-treatment LVEF assessment. Rationale for/against LVEF assessment was rarely documented: low CV risk was recorded as rationale for no LVEF assessment in 2 subjects. Among AYAs who underwent pre-treatment LVEF assessment, no significant abnormalities were detected and no changes in subsequent treatment plans were found. During median follow-up of 6.7 (inter-quartile range 5.4-9.5) years, 6/115 (5%) experienced CV events. Only 2 (1.7%) survivors experienced potential anthracycline-related CV events: 1 moderate cardiomyopathy at 9 years, 1 peri-partum cardiomyopathy and atrial fibrillation due to post-radiation SVC occlusion at 15 years post-treatment. Both these AYAs (aged 38 and 31 years at time of CV events) also had other CV risk factors- family history, smoking, obesity, and hyperlipidemia. Four (3.5%) survivors’ experienced CV events (1 sinus tachyarrhythmia, 1 junctional rhythm, 2 acute/asymptomatic drop in LVEF) unrelated to anthracyclines with clear alternative etiology e.g. sepsis/symptom burden. There was no correlation between having pre-treatment LVEF assessment and occurrence of CV events. 13/115 (11.3%) developed new CV risk factors: 4 hypertension, 6 hyperlipidemia, 3 diabetes. Conclusions: Pre-treatment LVEF assessment is done inconsistently in AYA lymphoma patients but does not impact initial treatment or predict late cardiotoxicity. CV events in long-term AYA lymphoma survivors are rare but evaluation of CV risk factors, early detection and management may be more important than focusing on LVEF assessment.

Monoclonal Antibody-Based Immunotherapy and Its Role in the Development of Cardiac Toxicity

Immunotherapy is one of the most effective therapeutic options for cancer patients. Five specific classes of immunotherapies, which includes cell-based chimeric antigenic receptor T-cells, checkpoint inhibitors, cancer vaccines, antibody-based targeted therapies, and oncolytic viruses. Immunotherapies can improve survival rates among cancer patients. At the same time, however, they can cause inflammation and promote adverse cardiac immune modulation and cardiac failure among some cancer patients as late as five to ten years following immunotherapy. In this review, we discuss cardiotoxicity associated with immunotherapy. We also propose using human-induced pluripotent stem cell-derived cardiomyocytes/ cardiac-stromal progenitor cells and cardiac organoid cultures as innovative experimental model systems to (1) mimic clinical treatment, resulting in reproducible data, and (2) promote the identification of immunotherapy-induced biomarkers of both early and late cardiotoxicity. Finally, we introduce the integration of omics-derived high-volume data and cardiac biology as a pathway toward the discovery of new and efficient non-toxic immunotherapy.

Cardiotoxicity - the first cause of morbidity and mortality in pediatric patients survivors of acute lymphoblastic leukemia

Acute lymphoblastic leukemia is the most common hematological malignancy at pediatric age. Cardiotoxicity holds the first place among the causes of morbidity and mortality in these patients. Anthracyclines are cytostatic drugs frequently associated with cardiotoxicity. Early diagnosis of cardiac impairment during the treatment of pediatric patients is extremely important, both for modulating future chemotherapy and for administering cardioprotective agents. Long term monitoring after chemotherapy helps to identify the risk of late cardiotoxicity among cancer survivors. There are several biomarkers, already in use or still under study, which may represent an operator-independent alternative for echocardiography in the diagnosis of cardiotoxicity. In case of cardiac damage, the clinician has options for treating or limiting the progression, either with the use of already approved agents, such as Dexrazoxane, or by administrating other cardioprotective drugs. International experts are still attempting to establish the best algorithm for early detection of cardiotoxicity, as well as the most efficient treatment plan in case of already existing myocardial damage in these patients. We present a review on treatment-related cardiotoxicity, including mechanisms of development, useful biomarkers and treatment options, after carefully analyzing specialty literature.

P1558 Diagnosis and prediction of late cardiotoxicity in non Hodgkin"s lymphoma by 3D echocardiography, vascular ultrasound, and cardiac biomarkers

Funding Acknowledgements Grant PCCDI 83/2018 (BIOVEA) and PN-III-P1-1-TE-2016-0669 CHOP chemotherapy in non-Hodgkin"s lymphoma (NHL) is limited by the risk of cardiotoxicity. Aim. To define new parameters, such as 3D LV deformation, arterial stiffness and biomarkers able to detect late cardiotoxicity. Methods. 69 patients (29 men, 59 ± 11 years) with NHL, scheduled to receive CHOP, with LVEF > 50%, were assessed at baseline, at the end of chemotherapy and 1.5 years after therapy completion by 3D echo for LV EF and deformation-longitudinal, radial, circumferential, area strain (LS, RS, CS, AS), by Echo-tracking for pulse wave velocity (PWV) and by biomarkers (troponin I, NTproBNP). Cardiotoxicity was defined as a decrease of LVEF <50%, with >10% from the baseline value. Results. 12 patients (group I) developed cardiotoxicity, while 57 patients did not (group II). There was a significant reduction of LS, CS, AS and an increase of arterial stiffness, but group I had greater changes (p = 0.001) (table). LVEF decrease correlated with changes of LS, AS, PWV and troponin (r = 0.62,r = 0.46,r=-0.33,r=-0.31, p < 0.05). LS reduction at the end of chemotherapy was the best independent predictor for LVEF decrease after 1.5 years from therapy completion (R²=0.41, p = 0.002). LS decrease with more than 23% at the end of treatment predicted late cardiotoxicity after 1.5 years (sensitivity of 84%; specificity of 73%). Conclusion. Assessment of 3D myocardial deformation, arterial stiffness and biomarkers is able to detect late cardiotoxicity and to predict further LVEF decline in NHL. LV deformation and vascular parameters CHOP Group I Group II LS(-%) Baseline 22 ± 2 22 ± 2 Final 15 ± 2† 19 ± 2† After 1.5years 12 ± 1† 17 ± 1† CS(-%) Baseline 21 ± 2 21 ± 2 Final 15 ± 1† 18 ± 2 After 1.5years 13 ± 1† 16 ± 1† AS(%) Baseline 37 ± 3 38 ± 2 Final 29 ± 3† 35 ± 2† After 1.5years 25 ± 2† 32 ± 1† PWV(m/s) Baseline 7.1 ± 1.2 7.1 ± 0.9 Final 8.8 ± 1.1† 7.4 ± 1.1† After1.5years 10.4 ± 1.0† 8.1 ± 1.2† LS longitudinal strain; CS circumferential strain; AS area strain; PWV pulse wave velocity. † p < 0.001.

P6893D echocardiography, arterial stiffness, and biomarkers for detection and prediction of late cardiotoxicity in non-Hodgkin lymphoma

CHOP chemotherapy (cyclophosphamide, doxorubicin, vincristine, prednisone) in non-Hodgkin lymphoma (NHL) is limited by risk of cardiotoxicity. Aim. To define new parameters to detect late cardiotoxicity. Methods 64 patients (27 men, 59±11 years) with NHL, scheduled for CHOP, with LVEF>50%, were assessed at baseline, after chemotherapy ended and 1 year later, by 3D echo for LVEF and deformation (longitudinal, radial, circumferential, area strain: LS, RS, CS, AS), by echo-tracking for pulse wave velocity (PWV) and wave intensity (WI), and by troponin I and NTproBNP. Cardiotoxicity was defined as LVEF decrease<50%, with >10% from baseline. Results 10 patients (group I) developed late cardiotoxicity, while 54 patients did not (group II). There was a reduction of LS, CS, AS, and increase of PWV and WI, with greater changes in group I (table). LVEF decrease correlated with LS, CS, AS, PWV, WI, troponin changes (r=0.57, r=0.37, r=0.41, r=−0.53, r=−0.43, r=−0.34 p<0.05). LS reduction after chemotherapy ended was the best independent predictor for LVEF decrease 1 year after therapy completion (R2=0.42 p=0.001). Decrease of LS >22% at the end of treatment predicted late cardiotoxicity with 85% sensitivity and 74% specificity. Late cardiovascular toxicity parametrs CHOP Group I Group II LS (-%) Baseline 22±2 21±2 Final 14±2† 18±2† After 1 year 11±1† 16±2† CS (-%) Baseline 21±2 21±2 Final 16±2† 19±2† After 1 year 13±2† 15±1† AS (%) Baseline 39±3 40±2 Final 33±2† 37±2† After 1 year 28±2† 35±1 PWV (m/s) Baseline 3.4±1.2 3.3±0.7 Final 6.9±1.5† 4.3±1.4† After 1 year 8.9±2.1† 5.5±1.3† WI (m/s) Baseline 4.2±0.8 4.4±0.6 Final 7.7±1.4† 5.1±0.8† After 1 year 9.4±0.9† 6.1±0.9† Abbreviations in text. †p<0.001. Conclusion Assessment of 3D myocardial deformation is able to detect late cardiovascular toxicity, and to predict further LVEF decline in NHL patients. Acknowledgement/Funding Grant PCCDI 83/2018 (BIOVEA)