Cancer Therapy-related Cardiac Dysfunction Research Articles

Abstract PO2-20-06: Using the Australian Cardio-Oncology Registry to study long-term cancer therapy related cardiac dysfunction in adult oncology patients – The Chris O’Brien Lifehouse experience

Abstract Background Cancer therapy related cardiac dysfunction (CTRCD) is a significant side effect of several chemotherapies, targeted agents, and immunotherapies integral to treatment. Anthracyclines are an example of a commonly used chemotherapy drug class that can cause irreversible early and late onset heart failure. CTRCD often leads to dose reductions and treatment delays or cessation, limiting treatment success and contributing to increased mortality and life-long morbidity in oncology survivors. In Australia, there are currently no multi-centre, longitudinal studies examining CTRCD in adult oncology patients. Trial design The Australian Cardiology-Oncology Registry (ACOR) is a prospective observational non-interventional study involving 14 sites across Australia. Patient information is obtained from hospital medical records and de-identified upon entry into the registry. Patient demographics, medical history, cancer diagnosis, treatment, cardiac evaluations, and the management of demonstrated CTRCD are recorded. Data is collected at baseline (prior to treatment), and then at six-monthly intervals thereafter. Additionally, patients who develop anthracycline-induced cardiotoxicity (ACT) will be asked to participate in the biobanking study, which will involve a one-off 12mL peripheral blood draw that will be processed at an external site for whole genome exome sequencing and the development of pluripotent derived stem cell cardiomyocytes. Eligibility criteria Inclusion Criteria • Adult oncology patients (>18+ years of age) treated with cardiotoxic therapies within the last 5-years Exclusion Criteria • Diagnosis of Trisomy 21 • Patients being treated with palliative intent Specific aims Chris O’Brien Lifehouse aims to use the ACOR to explore the epidemiology, clinical presentation, and management of CTRCD amongst adult oncology patients receiving cardiotoxic therapies. In addition, a biobanking sub-study will attempt to identify gene polymorphisms predisposing individuals to developing ACT. It is hoped that such longitudinal data collection can lead to the introduction of an ACT susceptibility genetic screening test allowing for the inclusion of patient risk stratification prior to anthracycline exposure in routine cancer treatment. Statistical methods Descriptive statistics will be used for variables for quantitative analysis. Kaplan Meier analyses will be used for survival curves, freedom from cardiac failure since enrolment and freedom from arrhythmia since enrolment. An annual report will be produced. Present accrual and target accrual At the time of submission, 224 adult oncology patients have been recruited to the ACOR via Chris O’Brien Lifehouse with the opening of the biobanking sub-study currently in progress. The ACOR anticipates with full registered site capacity to capture 600 patients annually. Citation Format: Jocelyn Finney, Ben Felmingham, Sanjeev Kumar, Alina Mahmood, Lisa Horvath, David Celermajer, Rachel Conyers. Using the Australian Cardio-Oncology Registry to study long-term cancer therapy related cardiac dysfunction in adult oncology patients – The Chris O’Brien Lifehouse experience [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-20-06.

Relevance of Cardiovascular Exercise in Cancer and Cancer Therapy-Related Cardiac Dysfunction.

Cancer therapy-related cardiac dysfunction (CTRCD) has been identified as a threat to overall and cancer-related survival. Although aerobic exercise training (AET) has been shown to improve cardiorespiratory fitness (CRF), the relationship between specific exercise regimens and cancer survival, heart failure development, and reduction of CTRCD is unclear. In this review, we discuss the impact of AET on molecular pathways and the current literature of sports in the field of cardio-oncology. Cardio-oncological exercise trials have focused on variations of AET intensity by using moderate continuous and high intensity interval training, which are applicable, safe, and effective approaches to improve CRF. AET increases CRF, reduces cardiovascular morbidity and heart failure hospitalization and should thus be implemented as an adjunct to standard cancer therapy, although its long-term effect on CTRCD remains unknown. Despite modulating diverse molecular pathways, it remains unknown which exercise regimen, including variations of AET duration and frequency, is most suited to facilitate peripheral and central adaptations to exercise and improve survival in cancer patients.

Abstract PO5-26-03: Evaluation of cardiotoxicity in Mexican patients with Breast Cancer under neoadjuvant treatment by two-dimension speckle echocardiography

Abstract Background Cardiotoxicity is a major concern in breast cancer patients treated with anthracyclines or anti-HER-2 therapy. The assessment of left ventricular ejection fraction (LVEF) by transthoracic echocardiogram (TTE) has been the most common method to evaluate cardiotoxicity. Different TTE parameters have been studied to assess cardiotoxicity, we aimed to evaluate left atrial strain (LAS) as a parameter of diastolic cardiotoxicity in Mexican patients under neoadjuvant treatment. Methods We prospectively recruited patients with breast cancer under neoadjuvant treatment with anthracyclines and/or anti-HER-2 from March 2022 to present. The evaluation includes TTE, and troponin measurements before chemotherapy, and respective follow-ups at 3 and 6 months from the baseline. We enrolled 187 patients, 172 and 131 had completed the three and six-month follow-ups, respectively. We limited the analysis to patients we could assess cardiotoxicity status, defined according to the ESC 2022 guidelines. Clinical and echocardiographic parameters were compared according to cardiotoxicity status using Chi-squared, two-tailed t-tests or Wilcoxon tests, as appropriate. Results The mean time of follow-up at second assessment was 213 days. The patients are divided into cardiotoxicity and no cardiotoxicity group. We reported 81 events of cardiotoxicity if we include troponin measurement or 36 events if we only evaluate TTE measurements. The incidence of cardiotoxicity in this study was not related with common risk factors as high BMI, presence of hypertension/diabetes or smoking status, but it was statistically associated with the presence of elevated LDL cholesterol (p 0.026). Fourteen percent (14%) were HR-/HER-2 (+), 44% HR+/HER-2 (-), 25% HR+/HER-2 (+), and 17% triple negative subtype. Eightyfive percent (85%) of patients received anthracyclines, 28% in combination with anti-HER-2 treatment, 12% received double anti-HER-2 blockade anthracycline free. The accumulated dose of anthracycline didn’t differ between groups. The use of anthracyclines and double anti/HER blockade was statically associated with development of CTRCD (p < 0.01 and p < 0.01), respectively, but not with a single anti-HER-2 treatment. In troponin-based cardiotoxicity definition, at the three-month follow-up, those who developed cancer therapy-related cardiac dysfunction (CTRCD) had only statically significant lower LVEF (Table 1) with respect to basal assessment. LASr baseline, three months and six months was similar between groups. In the cardiotoxicity group without troponin measurement, we observed statically significant decreased LVEF and LV GLS at 3 months and six months, and tendency to decreased LASr with respect to basal evaluation. Conclusions In our cohort the only modifiable risk factor with impact in the development of CTRCD was dyslipidemia, specifically high LDL. The traditional chemotherapy schemas as anthracyclines and doble anti HER-2 blockade correlate with the development of cardiotoxicity, but not the use of anti-HER-2 as single agent. The addition of troponin measurement to cardiotoxicity definition detected a greater number of events in this study, but doesn’t reflect changes in ETT parameters as LV- GLS and LVEF at this time of follow up, which means structural changes induced by treatment take time and serological measurement of troponin can enhance sensitivity and allows early detection. Further follow up and ETT assessment are needed. Table 1. Cardiotoxicity events including or not troponin levels and TTE parameters. Citation Format: Haydee Williams-Sanchez, Jose Rodrigo Espinosa-Fernandez, Sandy Ruiz-Cruz, Areli Velazquez-Martinez, Nilda Espinola-Zavaleta, Enrique C. Guerra, Alexis D Aparicio-Ortiz, Aldo Cabello-Ganem, Santiago Luna-Alcalá, Leonardo Proaño-Bernal, Neftali Eduardo Antonio-Villa. Evaluation of cardiotoxicity in Mexican patients with Breast Cancer under neoadjuvant treatment by two-dimension speckle echocardiography [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-26-03.

Variants in structural cardiac genes in patients with cancer therapy-related cardiac dysfunction after anthracycline chemotherapy: a case control study

BackgroundVariants in cardiomyopathy genes have been identified in patients with cancer therapy-related cardiac dysfunction (CTRCD), suggesting a genetic predisposition for the development of CTRCD. The diagnostic yield of genetic testing in a CTRCD population compared to a cardiomyopathy patient cohort is not yet known and information on which genes should be assessed in this population is lacking.MethodsWe retrospectively included 46 cancer patients with a history of anthracycline induced CTRCD (defined as a decrease in left ventricular ejection fraction (LVEF) to < 50% and a ≥ 10% reduction from baseline by echocardiography). Genetic testing was performed for 59 established cardiomyopathy genes. Only variants of uncertain significance and (likely) pathogenic variants were included. Diagnostic yield of genetic testing was compared with a matched cohort of patients with dilated cardiomyopathy (DCM, n = 46) and a matched cohort of patients without cardiac disease (n = 111).ResultsAverage LVEF at time of CTRCD diagnosis was 30.1 ± 11.0%. Patients were 52.9 ± 14.6 years old at time of diagnosis and 30 (65.2%) were female. Most patients were treated for breast cancer or lymphoma, with a median doxorubicin equivalent dose of 300 mg/m2 [112.5-540.0]. A genetic variant, either pathogenic, likely pathogenic or of uncertain significance, was identified in 29/46 (63.0%) of patients with CTRCD, which is similar to the DCM cohort (34/46, 73.9%, p = 0.262), but significantly higher than in the negative control cohort (47/111, 39.6%, p = 0.018). Variants in TTN were the most prevalent in the CTRCD cohort (43% of all variants). All (likely) pathogenic variants identified in the CTRCD cohort were truncating variants in TTN.There were no significant differences in severity of CTRCD and in recovery rate in variant-harbouring individuals versus non-variant harbouring individuals.ConclusionsIn this case-control study, cancer patients with anthracycline-induced CTRCD have an increased burden of genetic variants in cardiomyopathy genes, similar to a DCM cohort. If validated in larger prospective studies, integration of genetic data in risk prediction models for CTRCD may guide cancer treatment. Moreover, genetic results have important clinical impact, both for the patient in the setting of precision medicine, as for the family members that will receive genetic counselling.

Cancer therapy related cardiac dysfunction as a result of Panitumumab

Panitumumab is a human immunoglobulin monoclonal antibody designed to target the epidermal growth factor receptor (EGFR) which is used in the treatment of metastatic colorectal cancer alone or in combination with chemotherapy. In this report, we present a case of new onset heart failure with reduced ejection fraction in a patient following panitumumab therapy. A 73-year-old gentleman with metastatic rectal adenocarcinoma presented to his local hospital with increased shortness of breath, two months after his first and only dose of panitumumab. A transthoracic echocardiogram demonstrated dilated left ventricle with global hypokinesis and an estimated left ventricular ejection fraction of 25%. Our patient underwent a comprehensive diagnostic assessment at his presentation, including ECG, transthoracic echocardiogram, cardiac magnetic resonance, computed tomography coronary angiography (CTCA), invasive coronary angiogram and 18F-FDG PET-CT. These investigations revealed no evidence of ischemic events or inflammatory processes that could account for the severe left ventricular dysfunction. To our knowledge, this is the first reported case of heart failure with reduced ejection fraction linked to panitumumab with subsequent deep phenotyping. The current guidelines do not recommend specific cardiovascular monitoring protocols for patients receiving anti-EGFR monoclonal antibodies. Until more data are available, it would be prudent to implement the same cardiovascular surveillance measures outlined for individuals receiving osimertinib, which is an EGFR tyrosine kinase inhibitor.

Myocardial extracellular volume derived from contrast-enhanced chest computed tomography in longitudinal evaluation of cardiac toxicity in patients treated with immune checkpoint inhibitors.

The immune-related adverse effects after immune checkpoint inhibitors (ICIs) treatment have always been a hot topic. Although the incidence of myocarditis is not high among the related adverse effects, the mortality rate is extremely high once it occurs. In the past, the risk of cancer therapy-related cardiac dysfunction (CTRCD) after drug treatment was evaluated based on imaging examinations, but this evaluation still had certain limitations. Currently, the extracellular volume (ECV) score measurement calculated using cardiac magnetic resonance T1 mapping has become a reliable method for evaluating myocardial toxicity and computed tomography (CT) examination may become an alternative. This study aimed to longitudinally evaluate the cardiac toxicity of patients treated with ICIs using myocardial ECV derived from contrast-enhanced chest CT. A total of 500 patients with III-IV lung cancer and esophageal cancer treated with ICIs were evaluated. Participants underwent baseline examination and at least 1 follow-up examination after treatment. Contrast-enhanced chest CT-ECV, left ventricular ejection fraction (LVEF), and measurement of cardiac troponin T (cTnT) were conducted before the first treatment, 3-6 months after the first treatment, and about 12 months after the first treatment, respectively. The ECV value of the middle part of the left ventricular septum was evaluated on CT venography and plain scan, the LVEF value was evaluated by color Doppler ultrasound, and the quantity of cTnT was detected by chemiluminescence. Cancer therapy-related cardiac dysfunction was recorded. The mean baseline LVEF value was 68.51%±4.81% (N0=500), and those of LVEF1, LVEF2, and LVEF3 were 68.77%±4.30%, 68.16%±3.59%, and 66.23%±4.20%, respectively (N1=500, N2=467, and N3=361, respectively). There was no significant difference between LVEF1, LVEF2, and LVEF0 (P1=0.095, P2=0.062), whereas LVEF3 was significantly lower than LVEF0 (P<0.001). The average baseline cTnT0 value was 7.42±3.95 (N0=500). The values of cTnT1, cTnT2, and cTnT3 were 10.05±11.40, 12.24±13.59, and 14.54±14.49, respectively (N1=500, N2=467, N3=361). The values of cTnT1, cTnT2, and cTnT3 were significantly higher than cTnT0 (P1<0.001, P2<0.001, P3<0.001). The average ECV0 was 47.14%±7.48% (N0=500). ECV1, ECV2, and ECV3 were 50.85%±6.79%, 53.44%±6.96% and 52.64%±7.58% respectively (N1=500, N2=467 and N3=361). ECV1, ECV2, and ECV3 were significantly higher than ECV0 (P1<0.001, P2<0.001, P3<0.001). CTRCD occurred in 49 patients. There were significant differences between the CTRCD (+) group and the CTRCD (-) group in cTnT1, cTnT2, and cTnT3 (P1<0.001, P2<0.001, and P3<0.001, respectively) and in ECV1, ECV2, and ECV3 (P1=0.039, P2=0.041, and P3=0.013, respectively). CT-ECV began to increase at the early stage after the treatment of ICIs. CT-ECV is a potential biomarker for dynamically monitoring the cardiac toxicity of tumor patients after receiving ICIs. ECV may be used to speculate the CTRCD caused by the treatment of ICIs.

Inflammation and acute cardiotoxicity in adult hematological patients treated with CAR-T cells: results from a pilot proof-of-concept study

AimsChimeric Antigen Receptor-T (CAR-T) cell infusion is a rapidly evolving antitumor therapy; however, cardiovascular (CV) complications, likely associated with cytokine release syndrome (CRS) and systemic inflammation, have been reported to occur. The CARdio-Tox study aimed at elucidating incidence and determinants of cardiotoxicity related to CAR-T cell therapy.MethodsPatients with blood malignancies candidate to CAR-T cells were prospectively evaluated by echocardiography at baseline and 7 and 30 days after infusion. The study endpoints were i) incidence of cancer therapy-related cardiac dysfunction (CTRCD), CTRCD were also balanced for any grade CRS, but CTRCD occurred of Cardiology Guidelines on Cardio-Oncology (decrements of left ventricular ejection fraction (LVEF) or global longitudinal strain (GLS) and/or elevations of cardiac biomarkers (high sensitivity troponin I, natriuretic peptides) and ii), correlations of echocardiographic metrics with inflammatory biomarkers.ResultsIncidence of CTRCD was high at 7 days (59,3%), particularly in subjects with CRS. The integrated definition of CTRCD allowed the identification of the majority of cases (50%). Moreover, early LVEF and GLS decrements were inversely correlated with fibrinogen and interleukin-2 receptor levels (p always ≤ 0.01).ConclusionsThere is a high incidence of early CTRCD in patients treated with CAR-T cells, and a link between CTRCD and inflammation can be demonstrated. Dedicated patient monitoring protocols are advised.Graphical

Abstract 6297: “They should get a cardiologist to be a part of the team when you first go”: A qualitative analysis of racial differences in the cancer care experience amongst breast cancer patients receiving cardiotoxic therapy

Abstract Background: Black breast cancer survivors are up to three times more likely to develop cancer therapy-related cardiac dysfunction (CTRCD) when compared to White survivors. Reasons behind this disparity are not fully understood, and studies examining these disparities have been limited. One contributor may be variations in communications about CTRCD risk and risk prevention strategies between providers and patients by race and ethnicity. This study assessed racial differences in Black versus White breast cancer patients with provider communication regarding cardiotoxic treatments. Methods: Study participants were recruited from a comprehensive cancer center. Eligibility included identifying as a Black/African American or White woman, a diagnosis of stage I-III breast cancer, and receipt of anthracyclines and/or trastuzumab. Semi-structured interviews were conducted with survivors. Interviews were audio-recorded, transcribed, and were reconciled using Dedoose. Results: Interviews were conducted with 16 survivors (8 Black, 8 White) with a median age at diagnosis of 53 years. Prior to starting treatment, 100% of white survivors reported that a provider discussed CTRCD risk, however only 75% black survivors reported CTRCD discussion. Although all women received information on prevention strategies including exercise and nutrition, there were differences in timing of information delivered. Black women desired to have information at the beginning of treatment, but no White women mentioned a desire to receive information earlier. A greater proportion of White women reported engaging in prevention strategies such as exercising and eating healthy during treatment. In terms of knowledge gained, 75% of White Women reported being satisfied with the information given regarding cardiotoxic risk and prevention whereas only 45% of Black women reported being satisfied.As 65% of Black women (vs. White) reported being less than satisfied with the information given, Black women were also more likely to recommend access to additional resources. For example, one Black woman suggested that “they [care team] should get a cardiologist to be a part of the team when they first go. Conclusion &amp; Implications: Fewer Black women reported being satisfied with their medical visits regarding CTRCD risk and prevention strategies. Racial differences in assessments of these experiences highlight opportunities to develop culturally-tailored communication interventions to reduce racial disparities in CTRCD; however, future research is needed to assess interpersonal aspects of care during the receipt of cardiotoxic treatment. Citation Format: Ashley Turner, America Vijil, Sara Gómez-Trillos, Victoria Williams, Paulette Omeaku, Susan Hong, Arnethea L. Sutton. “They should get a cardiologist to be a part of the team when you first go”: A qualitative analysis of racial differences in the cancer care experience amongst breast cancer patients receiving cardiotoxic therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6297.

Artificial intelligence-enabled prediction of chemotherapy-induced cardiotoxicity from baseline electrocardiograms

Anthracyclines can cause cancer therapy-related cardiac dysfunction (CTRCD) that adversely affects prognosis. Despite guideline recommendations, only half of the patients undergo surveillance echocardiograms. An AI model detecting reduced left ventricular ejection fraction from 12-lead electrocardiograms (ECG) (AI-EF model) suggests ECG features reflect left ventricular pathophysiology. We hypothesized that AI could predict CTRCD from baseline ECG, leveraging the AI-EF model’s insights, and developed the AI-CTRCD model using transfer learning on the AI-EF model. In 1011 anthracycline-treated patients, 8.7% experienced CTRCD. High AI-CTRCD scores indicated elevated CTRCD risk (hazard ratio (HR), 2.66; 95% CI 1.73–4.10; log-rank p < 0.001). This remained consistent after adjusting for risk factors (adjusted HR, 2.57; 95% CI 1.62–4.10; p < 0.001). AI-CTRCD score enhanced prediction beyond known factors (time-dependent AUC for 2 years: 0.78 with AI-CTRCD score vs. 0.74 without; p = 0.005). In conclusion, the AI model robustly stratified CTRCD risk from baseline ECG.

Automated segmentation of the left-ventricle from MRI with a fully convolutional network to investigate CTRCD in breast cancer patients.

Purpose: The goal of this study was to develop a fully convolutional network (FCN) tool to automatedly segment the left-ventricular (LV) myocardium in displacement encoding with stimulated echoes MRI. The segmentation results are used for LV chamber quantification and strain analyses in breast cancer patients susceptible to cancer therapy-related cardiac dysfunction (CTRCD). Approach: A DeepLabV3+ FCN with a ResNet-101 backbone was custom-designed to conduct chamber quantification on 45 female breast cancer datasets (23 training, 11 validation, and 11 test sets). LV structural parameters and LV ejection fraction (LVEF) were measured, and myocardial strains estimated with the radial point interpolation method. Myocardial classification validation was against quantization-based ground-truth with computations of accuracy, Dice score, average perpendicular distance (APD), Hausdorff-distance, and others. Additional validations were conducted with equivalence tests and Cronbach's alpha () intraclass correlation coefficients between the FCN and a vendor tool on chamber quantification and myocardial strain computations. Results: Myocardial classification results against ground-truth were , , and for the validation set and , , and for the test set. The confidence intervals (CI) and two one-sided t-test results of equivalence tests between the FCN and vendor-tool were to 2.42%, p-value < 0.001 for LVEF ( versus ), and to 0.63%, p-value < 0.001 for longitudinal strain ( versus ). Conclusions: The validation results were found equivalent to the vendor tool-based parameter estimates, which show that accurate LV chamber quantification followed by strain analysis for CTRCD investigation can be achieved with our proposed FCN methodology.

Arterial Stiffness May Predict Subsequent Cancer Therapy-Related Cardiac Dysfunction in Breast Cancer Patients

Cancer therapy-related cardiac dysfunction (CTRCD) is still a serious problem. Existing risk scores are insufficient for risk classification, especially in low and medium-risk patients. This study aims to evaluate if arterial stiffness (AS) measurement, which is associated with most of the known risk factors, can be a useful parameter for predicting subsequent CTRCD in patients with breast cancer (BC). Patients with BC were included in the study. All patients’ AS parameters such as pulse wave velocity (PWV), augmentation index (AIx), augmentation pressure (AP), and echocardiographic parameters were obtained before treatment. During treatment, echocardiographic follow-up with routine parameters and left ventricle global longitudinal strain (LVGLS) were measured. Patients were evaluated on whether CTRCD occurred or not. A total of 67 patients were analyzed. The mean age of the study population was 54.9 ± 11 years. Baseline characteristics were similar except for age. No CTRCD diagnosis was obtained according to left ventricle ejection fraction (LVEF) reduction, but 18 patients (26.8%) developed CTRCD regarding the decline in LVGLS. Left ventricle hypertrophy and diastolic dysfunction were more frequent in patients with CTRCD (p = 0.016 and p = 0.015, respectively). PWV, AIx, and AP as AS parameters were significantly higher in patients with CTRCD, but Alx@75 were not (p = 0.005, p = 0.034, p = 0.008, p = 0.077, respectively). A positive correlation between PWV and a decreased percent in LVGS (R = 0.607, p < 0.001) was observed. ROC curve analyses revealed an AUC of 0.747 (p = 0.02, 95% CI 0.632–0.832) for PWV. A PWV value of 9.2 m/s predicted CTRCD with 94% sensitivity and 73% specificity. AS measurement may be useful for predicting CTRCD in patients with low to medium-risk BC.Graphical

Subclinical myocardial damage after anthracycline chemotherapy in Japanese patients with breast cancer

BackgroundData on the incidence, timing, and severity of myocardial damage after anthracycline-based chemotherapy (AC) in Japanese patients with breast cancer are limited. MethodWe evaluated cancer therapy-related cardiac dysfunction (CTRCD) in Japanese women with breast cancer (n = 51) after the first AC according to the definitions of the 2022 European Society of Cardiology onco-cardiology guideline, including assessment of high-sensitivity troponin I (TnI) and B-type natriuretic peptide (BNP) levels. ResultsCTRCD was detected in 67 % of the patients (3.9 %, 7.8 %, 9.8 %, 43 %, 37 %, 22 %, 20 %, and 9.8 % of patients at 1 week and 1, 2, 3, 6, 9, 12, and 15 months post-AC, respectively) without significant left ventricular ejection fraction reduction (<50 %) and heart failure. Elevated TnI levels (>26 pg/mL) were found in 43 % of patients, and elevated BNP levels (≥35 pg/mL) were observed in 22 % of patients during the follow-up period. ConclusionsApproximately two-thirds of the Japanese patients in this study experienced CTRCD, which was frequently observed at 3 or 6 months post-AC. However, all patients with CTRCD were diagnosed with mild asymptomatic CTRCD. Although, these patients were diagnosed with mild asymptomatic CTRCD, careful long-term follow-up will be required.

Exercise-based cardio-oncology rehabilitation for cardiotoxicity prevention during breast Cancer chemotherapy: The ONCORE randomized controlled trial

BackgroundBreast cancer (BC) treatment with anthracyclines and/or anti-human epidermal growth factor receptor-2 (HER2) antibodies is associated with an increased risk of cardiovascular disease complications, including cancer therapy-related cardiac dysfunction (CTRCD). While Cardio-Oncology Rehabilitation (CORe) programs including exercise have emerged to minimize these risks, its role in preventing CTRCD is unclear. ObjectivesWe investigated the effectiveness of an exercise-based CORe program in preventing CTRCD [left ventricular ejection fraction (LVEF) drop ≥10% to a value <53% or a decrease >15% in global longitudinal strain (GLS)]. Secondary outcomes examined changes in cardiac biomarkers, physical performance including peak oxygen consumption, psychometric and lifestyle outcomes. Safety, adherence, and patient satisfaction were also assessed. MethodsThis is a randomized controlled trial including 122 early-stage BC women receiving anthracyclines and/or anti-HER2 antibodies, randomized to CORe (n = 60) or usual care with exercise recommendation (n = 62). Comprehensive assessments were performed at baseline and after cardiotoxic treatment completion. The average duration of the intervention was 5.8 months. ResultsNo cases of CTRCD were identified during the study. LVEF decreased in both groups, but was significantly attenuated in the CORe group [−1.5% (−2.9, −0.1); p = 0.006], with no changes detected in GLS or cardiac biomarkers. The CORe intervention led to significant body mass index (BMI) reduction (p = 0.037), especially in obese patients [3.1 kg/m2 (1.3, 4.8)]. Physical performance and quality-of-life remained stable, while physical activity level increased in both groups. No adverse events were detected. ConclusionsThis study suggests that CORe programs are safe and may help attenuate LVEF decline in BC women receiving cardiotoxic therapy and reduce BMI in obese patients.

Coronary Flow Velocity Reserve Declines After Anthracycline Therapy in Breast Cancer Patients

Anthracycline therapy (ANT) is associated with cancer therapy-related cardiac dysfunction. Coronary flow velocity reserve (CFVR) has shown prognostic utility in non-cancer cohorts, but no data have been obtained in a cardio-oncology setting. We investigated the acute effect of ANT on CFVR in breast cancer patients. A total of 12 female breast cancer patients undergoing ANT had pre- and post-ANT CFVR assessment. A significant decline in CFVR occurred (baseline: 2.66 ± 0.41 vs post-ANT: 2.47 ± 0.37, P = 0.016). This prospective study is the first to identify ANT-related coronary physiology changes in humans. Further studies are required to determine their clinical significance.

Features of trastuzumab-related cardiac dysfunction: deformation analysis outside left ventricular global longitudinal strain.

Cancer therapy-related cardiac dysfunction due to trastuzumab has been well-known for many years, and echocardiographic surveillance is recommended every 3 months in patients undergoing trastuzumab treatment, irrespective of the baseline cardiotoxicity risk. However, the potential harm and cost of overscreening in low- and moderate-risk patients have become great concerns. This study aimed to identify the incidence of early cancer therapy-related cardiac dysfunction (CTRCD) and the behaviours of left and right heart deformations during trastuzumab chemotherapy in low- and moderate-risk patients. We prospectively enrolled 110 anthracycline-naïve women with breast cancer and cardiovascular risk factors who were scheduled to receive trastuzumab. The left ventricular ejection fraction (LVEF), left ventricular global longitudinal strain (LV-GLS), and right ventricular and left atrial longitudinal strains were evaluated using echocardiography at baseline, before every subsequent cycle and 3 weeks after the final dose of trastuzumab. The baseline risk of CTRCD was graded according to the risk score proposed by the Heart Failure Association (HFA) Cardio-Oncology Working Group and the International Cardio-Oncology Society (ICOS). CTRCD and its severity were defined according to the current European Society of Cardiology (ESC) guidelines. Twelve (10.9%) patients had asymptomatic CTRCD. All CTRCD occurred sporadically during the first 9 months of the active trastuzumab regimen in both low- and moderate-risk patients. While CTRCD was graded as moderate severity in 41.7% of patients and heart failure therapy was initiated promptly, no irreversible cardiotoxicity or trastuzumab interruption was recorded at the end of follow-up. Among the left and right heart deformation indices, only LV-GLS decreased significantly in the CTRCD group during the trastuzumab regimen. CTRCD is prevalent in patients with non-high-risk breast cancer undergoing trastuzumab chemotherapy. Low- and moderate-risk patients show distinct responses to trastuzumab. The LV-GLS is the only deformation index sensitive to early trastuzumab-related cardiac dysfunction.

Impact of the ESC Cardio-Oncology Guidelines Biomarker Criteria on Incidence of Cancer Therapy–Related Cardiac Dysfunction

BackgroundThe impact of recent consensus definitions of cancer therapy–related cardiac dysfunction (CTRCD) from the European Society of Cardiology cardio-oncology guidelines on the reported incidence of CTRCD has not yet been assessed. ObjectivesThe aim of this study was to assess the: 1) cumulative incidence; 2) point prevalence during and after adjuvant therapy; and 3) prognostic value of CTRCD as defined by different asymptomatic CTRCD guideline criteria. MethodsThe cumulative incidence and point prevalence of CTRCD were retrospectively assessed in 118 patients participating in the PRADA (Prevention of Cardiac Dysfunction During Adjuvant Breast Cancer Therapy) trial. Asymptomatic CTRCD was assessed using alternative cardiac troponin (cTn) 99th percentile upper reference limits (URLs) to define cTnT and cTnI elevation. ResultsThe cumulative incidence of moderate or severe CTRCD was low (1.7%), whereas the cumulative incidence of mild asymptomatic CTRCD was higher and differed markedly according to the biomarker criteria applied, ranging from 49.2% of patients when cTnT greater than the sex-specific 99th percentile URL was used to define cTn elevation to 9.3% when sex-neutral cTnI was used. The point prevalence of CTRCD was highest at the end of anthracycline therapy (47.8%) and was driven primarily by asymptomatic cTn elevation. CTRCD during adjuvant therapy was not prognostic for CTRCD at extended follow-up of 24 months (Q1-Q3: 21-29 months) after randomization. ConclusionsMild asymptomatic CTRCD during adjuvant breast cancer therapy was frequent and driven mainly by cTn elevation and was not prognostic of subsequent CTRCD. The incidence of mild, asymptomatic CTRCD differed markedly depending on the cTn assay and whether sex-neutral or sex-dependent URLs were applied. (Prevention of Cardiac Dysfunction During Adjuvant Breast Cancer Therapy [PRADA]; NCT01434134)

Cardiovascular magnetic resonance characterization of myocardial tissue injury in a miniature swine model of cancer therapy-related cardiovascular toxicity

BackgroundLeft ventricular ejection fraction (LVEF) is the most commonly clinically used imaging parameter for assessing cancer therapy-related cardiac dysfunction (CTRCD). However, LVEF declines may occur late, after substantial injury. This study sought to investigate cardiovascular magnetic resonance (CMR) imaging markers of subclinical cardiac injury in a miniature swine model. MethodsFemale Yucatan miniature swine (n=14) received doxorubicin (2mg/kg) every 3 weeks for 4 cycles. CMR, including cine, tissue characterization via T1 and T2 mapping, and late gadolinium enhancement (LGE) was performed on the same day as doxorubicin administration and three weeks after the final chemotherapy cycle. In addition, MR spectroscopy (MRS) was performed during the 3 weeks after the final chemotherapy in 7 pigs. A single CMR and MRS exam was also performed in three Yucatan miniature swine that were age- and weight-matched to the final imaging exam of the doxorubicin-treated swine to serve as controls. CTRCD was defined as histological early morphologic changes, including cytoplasmic vacuolization and myofibrillar loss of myocytes, based on post-mortem analysis of humanely euthanized pigs after the final CMR exam. ResultsOf 13 swine completing five serial CMR scans, 10 (77%) had histological evidence of CTRCD. Three animals had neither histological evidence nor changes in LVEF from baseline. No absolute LVEF <40% or LGE were observed. Native T1, extracellular volume (ECV), and T2 at 12 weeks were significantly higher in swine with CTRCD than those without CTRCD (1178 ms vs. 1134 ms, p=0.002, 27.4% vs. 24.5%, p=0.03, and 38.1 ms vs. 36.4 ms, p=0.02, respectively). There were no significant changes in strain parameters. The temporal trajectories in native T1, ECV, and T2 in swine with CTRCD showed similar and statistically significant increases. At the same time, there were no differences in their temporal changes between those with and without CTRCD. MRS myocardial triglyceride content substantially differed among controls, swine with and without CTRCD (0.89%, 0.30%, 0.54%, respectively, ANOVA, p=0.01), and associated with the severity of histological findings and incidence of vacuolated cardiomyocytes. ConclusionsSerial CMR imaging alone has a limited ability to detect histologic CTRCD beyond LVEF. Integrating MRS myocardial triglyceride content may be useful for detection of early potential CTRCD.

Effect of variable left ventricular ejection fraction assessed by equilibrium radionuclide angiocardiography using different software packages on the diagnosis of cardiotoxicity in patients with cancer

BackgroundThe equilibrium radionuclide angiocardiography (ERNA) scan is an established imaging modality for assessing left ventricular ejection fraction (LVEF) in oncology patients. This study aimed to explore the interchangeability of two commercially available software packages (MIM and JS) for LVEF measurement for a cancer-therapy-related cardiac dysfunction (CTRCD) diagnosis. MethodsThis is a single-center retrospective study among 322 patients who underwent ERNA scans. A total of 582 scans were re-processed using MIM and JS for cross-sectional and longitudinal LVEF measurements. ResultsThe median LVEF for MIM and JS were 56% and 66%, respectively (P < 0.001). LVEF processed by JS was 9.91% higher than by MIM. In 87 patients with longitudinal ERNA scans, serial studies processed by MIM were classified as having CTRCD in a higher proportion than serial studies processed by JS (26.4% vs 11.4%, P = 0.020). There were no significant differences in intra- or inter-observer LVEF measurement variability (R = 0.99, P < 0.001). ConclusionsSoftware packages for processing ERNA studies are not interchangeable; thus, reports of ERNA studies should include details on the post-processing software. Serial ERNA studies should be processed on the same software when feasible to avoid discrepancies in the diagnosis and management of CTRCD.

Atrial Strain Assessment for the Early Detection of Cancer Therapy-Related Cardiac Dysfunction in Breast Cancer Women (The STRANO STUDY: Atrial Strain in Cardio-Oncology).

Left ventricular global longitudinal strain (GLS) has an important role in the diagnosis of cancer therapy-related cardiac dysfunction (CTRCD). Little is known about the role of atrial function in diagnosing CTRCD. The aim of our study was to assess the impact of anti-cancer drugs on atrial function measured by speckle-tracking echocardiography in breast cancer women. A prospective multicenter study was conducted enrolling 169 breast cancer women treated with anthracyclines. A cardiological evaluation including an electrocardiogram and echocardiogram with an analysis of GLS, left atrial (LA) strain, and LA stiffness (LASi) was performed at baseline (T0), 3 (T1), and 6 months (T2) after starting chemotherapy. The patients were divided into two groups: patients with asymptomatic mild cardiotoxicity at T1 (with a relative reduction in GLS > 15%; Group 1) and those without (Group 2). We did not find a significant change in left ventricular ejection fraction (LVEF) at T1 and T2; we found a significant change in GLS (p-value < 0.0001) in the peak atrial longitudinal strain (PALS) and in LASi (p-value < 0.0001). Impairment of atrial function was greater in Group 1 compared to Group 2. A PALS variation > 20.8% identified patients who were most likely to develop asymptomatic mild cardiotoxicity [AUC 0.62; CI (0.51-0.73) p = 0.06, sensitivity 45%, specificity 69.5%]. Conclusions: PALS and LASi significantly change during chemotherapy in association with GLS. Atrial strain is an additional parameter that could be measured together with GLS to detect cardiotoxicity early.

The use of high sensitivity troponin T as a biomarker of anthracycline cardiotoxicity

Abstract Introduction Anthracyclines are a highly effective class of chemotherapy used to treat a wide variety of malignancies. Their use is complicated by the development of cancer therapy-related cardiac dysfunction (CT-RCD), defined broadly as the development of left ventricular systolic dysfunction following cancer treatment. Troponin, a well-established marker of myocardial necrosis and early myocardial injury following anthracycline chemotherapy, may predict the subsequent development of CT-RCD. It is not known, however, at what timepoint troponin should be measured, or if there is a clinically relevant threshold that best predicts the development of CT-RCD. Purpose 1. To investigate if high sensitivity troponin T (hsTnT) accurately predicts the development of anthracycline CT-RCD 2. To establish the best timepoint at which hsTnT should be measured to predict CT-RCD 3. To establish the most clinically relevant hsTnT concentration to predict CT-RCD Methods In 2020 we introduced a clinical pathway for outpatients receiving anthracycline chemotherapy at our Institution. As part of this pathway, hsTnT concentrations are measured at baseline (pre-chemotherapy) and prior to each anthracycline cycle. In this study, we performed a prospective audit of outpatients receiving anthracycline chemotherapy for the treatment of breast or haematological malignancies. Troponin concentrations prior to each chemotherapy cycle were assessed and ROC curve analyses were performed to determine the most accurate timepoint and threshold to predict CT-RCD. CT-RCD was defined as a drop in the left ventricular ejection fraction (LVEF) of &amp;gt;10% from baseline to a value of &amp;lt;50%. Results 118 outpatients were treated with anthracycline chemotherapy between August 2020 and May 2022. 64 patients (54%) were treated for breast cancer and 54 (46%) for haematological malignancies. The mean age was 54±15yrs, with 71% females. At baseline, 27 (23%) of patients had a diagnosis of hypertension, 16 (14%) diabetes, 28 (24%) smoking history, 10 (8%) chronic kidney disease and 31 (26%) obesity. The median cumulative dose was 360mg/m² for Epirubicin and 300mg/m² for Doxorubicin. The baseline mean LVEF was 60.5±4%. 97/118 (82%) of patients had a follow up echocardiogram. 11/97 (11%) of patients developed CT-RCD. Mean hsTnT concentrations rose incrementally as the cumulative dose of anthracycline increased (Fig 1). Baseline hsTnT concentration was the most accurate predictor of subsequent CT-RCD (AUC 0.75), with a 75% sensitivity and 80% specificity for predicting CT-RCD if the baseline hsTnT concentration was ≥10.5ng/L. In addition, the baseline mean hsTnT concentration was significantly higher in patients with CT-RCD vs. those with no CT-RCD, P=0.0008 (Fig 2). Conclusions High sensitivity troponin T concentrations appear to be clinically useful in predicting subsequent CT-RCD, with the most accurate point of measurement being at baseline, prior to chemotherapy commencing.