Serum Carnitine Concentrations and Cardiac Function in Pediatric, Adolescent and Young Adult Oncology Patients Receiving High-Dose Anthracyclines.

OBJECTIVE: Anthracycline chemotherapy agents have significant dose-dependent cardiotoxic effects. -Carnitine, a non-essential amino acid, is involved in long chain fatty acid oxidation, and carnitine deficiency can result in cardiomyopathy and cardiac arrhythmias. If administered concurrently with chemotherapy, carnitine supplementation could be a potential strategy to prevent cardiotoxicity. However, the association between serum carnitine concentrations and anthracycline cardiotoxicity during cancer treatment in the childhood, adolescent, and young adult (CAYA) age range has not been established. METHODS: This prospective pilot cohort study characterized changes in serum carnitine concentrations and cardiac function before, during, and approximately 1 year after large-dose anthracycline therapy in newly diagnosed CAYA cancer patients. RESULTS: Among 21 patients with a mean cumulative anthracycline dose exposure of 409 mg/m2 of -doxorubicin equivalents, left ventricular ejection fraction and relative wall thickness decreased, indicating an overall decline in cardiac function. A reversible decrease in serum carnitine concentrations was also observed. A non-statistically significant positive correlation was observed; for every 1 mmol/L decrease in serum carnitine concentration, there was a 0.09% decrease in LVEF (p = 0.2). CONCLUSIONS: These findings from this small pilot study suggest that there may be a relationship between serum carnitine concentrations and cardiac function after anthracycline therapy that should be evaluated in larger studies.

Feasibility, reproducibility, and accuracy of echocardiographic right ventricular systolic function assessments in childhood cancer survivors at risk for heart failure.

PURPOSE: We sought to assess the feasibility, reproducibility, and accuracy of conventional and newer echocardiographic measures of right ventricular (RV) systolic function in adolescent and young adult childhood cancer survivors treated with anthracyclines. METHODS: Echocardiography and cardiac magnetic resonance imaging (CMR) were acquired ≤60 days apart in prospectively recruited survivors and RV functional measures were quantitated by blinded observers. Repeat quantitation was performed in a subset to evaluate reproducibility. For each echocardiographic measure, Spearman correlations with CMR measures were calculated, and values in participants with CMR RV ejection fraction (RVEF) ≥48% and RVEF <48% were compared using two sample Wilcoxon rank-sum tests. RESULTS: Among 58 participants, mean age was 18.2 years (range 13.1-25.2) and five participants had CMR RVEF <48%. Intra- and inter-observer coefficients of variation were 8.2%-10.1% and 10.5%-12.0% for adjusted automated strain measures, and 5.2%-8.7% and 2.7% for 3D RVEF, respectively. No echocardiographic measures were significantly correlated with CMR RVEF; only tricuspid annular plane systolic excursion was correlated with CMR RV stroke volume (r = .392, p = .003). Participants with RV dysfunction had worse automated global longitudinal strain (-20.3% vs. -23.9%, p = .007) and free wall longitudinal strain (-23.7% vs. -26.7%, p = .09). CONCLUSIONS: Echocardiographic strain and 3D RV function measurements were feasible and reproducible in at-risk childhood cancer survivors. Although not associated with CMR RVEF in this population with predominantly normal RV function, automated strain measurements were more abnormal in participants with RV dysfunction, suggesting potential clinical utility of these measures.

Cardiotoxicity of CPX-351 in children and adolescents with relapsed AML: a Children's Oncology Group report.

Introduction: Anthracyclines are effective in treating acute myeloid leukemia (AML) but limited by cardiotoxicity. CPX-351, a liposomal daunorubicin and cytarabine, may provide therapeutic benefit with less cardiotoxicity. Acute changes in left ventricular systolic function and cardiac biomarkers were evaluated after a cycle of CPX-351 in children with relapsed AML treated on the phase 1/2 Children's Oncology Group study, AAML1421. Methods: Subjects received 135 units/m2/dose of CPX-351 on days 1, 3, and 5 as cycle 1. Echocardiograms were performed and centrally quantitated at baseline and at the end of cycle 1 (day 29 +/- 1 week). High sensitivity troponin (hs-cTnT) and N-terminal pro-B-type natriuretic peptide (NT-proBNP) were measured at baseline and serially through the end of cycle 1 (days 5, 8, 15, 22 and 29). Differences between baseline and post-CPX-351 echo/biomarker measures were analyzed using Wilcoxon signed rank tests. Linear regression was used to model post-CPX-351 left ventricular ejection fraction (LVEF) with cTnT/NT-proBNP at each time point, controlling for baseline LVEF. Cancer therapy related cardiac dysfunction (CTRCD) was defined as a decline in LVEF of ≥10%-<50%. Results: Twenty-five of 38 heavily anthracycline pre-treated (median 348 mg/m2 daunorubicin equivalents) subjects enrolled on AAML1421 were included in the cardiac analyses. At baseline, centrally quantitated LVEF was <50% in 8 of 25 subjects (32%) with a median LVEF of 53.8% [48.0, 56.9]. Following CPX-351, LVEF declined significantly (ΔLVEF -3.3% [-7.8, 0]) and 6 of 25 subjects (24%) experienced CTRCD. Amongst all subjects, hs-cTnT was modestly increased at end of cycle 1 compared to baseline [baseline hs-cTnT 7.2 (3, 10.6); ΔcTnT 1.80 (0, 6.1), p = 0.03]. NT-proBNP remained stably elevated without significant change. No significant associations were seen between NT-proBNP or cTnT levels and post-CPX-351 LVEF. Discussion: In this single arm study of anthracycline pre-treated children exposed to CPX-351, baseline abnormalities in cardiovascular function were prevalent. Following CPX-351, LVEF decreased, cTnT increased, and NT-proBNP did not change. Longer follow-up is needed to determine whether these changes result in clinically meaningful long-term decrements in cardiac function. An ongoing randomized trial of CPX-351 compared to standard anthracyclines in anthracycline naïve patients will provide further insight into the cardiac effects of CPX-351 (ClinicalTrials.gov; NCT04293562).

Feasibility of a Health Coach Intervention to Reduce Sitting Time and Improve Physical Functioning Among Breast Cancer Survivors: Pilot Intervention Study.

BACKGROUND: Sedentary behavior among breast cancer survivors is associated with increased risk of poor physical function and worse quality of life. While moderate to vigorous physical activity can improve outcomes for cancer survivors, many are unable to engage in that intensity of physical activity. Decreasing sitting time may be a more feasible behavioral target to potentially mitigate the impact of cancer and its treatments. OBJECTIVE: The purpose of this study was to investigate the feasibility and preliminary impact of an intervention to reduce sitting time on changes to physical function and quality of life in breast cancer survivors, from baseline to a 3-month follow-up. METHODS: Female breast cancer survivors with self-reported difficulties with physical function received one-on-one, in-person personalized health coaching sessions aimed at reducing sitting time. At baseline and follow-up, participants wore the activPAL (thigh-worn accelerometer; PAL Technologies) for 3 months and completed physical function tests (4-Meter Walk Test, Timed Up and Go, and 30-Second Chair Stand) and Patient-Reported Outcomes Measurement Information System (PROMIS) self-reported outcomes. Changes in physical function and sedentary behavior outcomes were assessed by linear mixed models. RESULTS: On average, participants (n=20) were aged 64.5 (SD 9.4) years; had a BMI of 30.4 (SD 4.5) kg/m2; and identified as Black or African American (n=3, 15%), Hispanic or Latina (n=4, 20%), and non-Hispanic White (n=14, 55%). Average time since diagnosis was 5.8 (SD 2.2) years with participants receiving chemotherapy (n=8, 40%), radiotherapy (n=18, 90%), or endocrine therapy (n=17, 85%). The intervention led to significant reductions in sitting time: activPAL average daily sitting time decreased from 645.7 (SD 72.4) to 532.7 (SD 142.1; ß=-112.9; P=.001) minutes and average daily long sitting bouts (bout length ≥20 min) decreased from 468.3 (SD 94.9) to 366.9 (SD 150.4; ß=-101.4; P=.002) minutes. All physical function tests had significant improvements: on average, 4-Meter Walk Test performance decreased from 4.23 (SD 0.95) to 3.61 (SD 2.53; ß=-.63; P=.002) seconds, Timed Up and Go performance decreased from 10.30 (SD 3.32) to 8.84 (SD 1.58; ß=-1.46; P=.003) seconds, and 30-Second Chair Stand performance increased from 9.75 (SD 2.81) to 13.20 completions (SD 2.53; ß=3.45; P<.001). PROMIS self-reported physical function score improved from 44.59 (SD 4.40) to 47.12 (SD 5.68; ß=2.53; P=.05) and average fatigue decreased from 52.51 (SD 10.38) to 47.73 (SD 8.43; ß=-4.78; P=.02). CONCLUSIONS: This 3-month pilot study suggests that decreasing time spent sitting may be helpful for breast cancer survivors experiencing difficulties with physical function and fatigue. Reducing sitting time is a novel and potentially more feasible approach to improving health and quality of life in cancer survivors.

Rationale and design of the Children's Oncology Group study AAML1831 integrated cardiac substudies in pediatric acute myeloid leukemia therapy.

Background: Pediatric acute myeloid leukemia (AML) therapy is associated with substantial short- and long-term treatment-related cardiotoxicity mainly due to high-dose anthracycline exposure. Early left ventricular systolic dysfunction (LVSD) compromises anthracycline delivery and is associated with inferior event-free and overall survival in de novo pediatric AML. Thus, effective cardioprotective strategies and cardiotoxicity risk predictors are critical to optimize cancer therapy delivery and enable early interventions to prevent progressive LVSD. While dexrazoxane-based cardioprotection reduces short-term cardiotoxicity without compromising cancer survival, liposomal anthracycline formulations have the potential to mitigate cardiotoxicity while improving antitumor efficacy. This overview summarizes the rationale and methodology of cardiac substudies within AAML1831, a randomized Children's Oncology Group Phase 3 study of CPX-351, a liposomal formulation of daunorubicin and cytarabine, in comparison with standard daunorubicin/cytarabine with dexrazoxane in the treatment of de novo pediatric AML. Methods/design: Children (age <22 years) with newly diagnosed AML were enrolled and randomized to CPX-351-containing induction 1 and 2 (Arm A) or standard daunorubicin and dexrazoxane-containing induction (Arm B). Embedded cardiac correlative studies aim to compare the efficacy of this liposomal anthracycline formulation to dexrazoxane for primary prevention of cardiotoxicity by detailed core lab analysis of standardized echocardiograms and serial cardiac biomarkers throughout AML therapy and in follow-up. In addition, AAML1831 will assess the ability of early changes in sensitive echo indices (e.g., global longitudinal strain) and cardiac biomarkers (e.g., troponin and natriuretic peptides) to predict subsequent LVSD. Finally, AAML1831 establishes expert consensus-based strategies in cardiac monitoring and anthracycline dose modification to balance the potentially competing priorities of cardiotoxicity reduction with optimal leukemia therapy. Discussion: This study will inform diagnostic, prognostic, preventative, and treatment strategies regarding cardiotoxicity during pediatric AML therapy. Together, these measures have the potential to improve leukemia-free and overall survival and long-term cardiovascular health in children with AML. Clinical trial registration: https://clinicaltrials.gov/, identifier NCT04293562.

Myocardial Regional Shortening from 4D Cardiac CT Angiography for the Detection of Left Ventricular Segmental Wall Motion Abnormality.

Purpose: To investigate whether endocardial regional shortening computed from four-dimensional (4D) CT angiography (RSCT) can be used as a decision classifier to detect the presence of left ventricular (LV) wall motion abnormalities (WMAs). Materials and Methods: One hundred electrocardiographically gated cardiac 4D CT studies (mean age, 59 years ± 14 [SD]; 61 male patients) conducted between April 2018 and December 2020 were retrospectively evaluated. Three experts labeled LV wall motion in each of the 16 American Heart Association (AHA) segments as normal or abnormal; they also measured peak RSCT across one heartbeat in each segment. The data set was split evenly into training and validation groups. During training, interchangeability of RSCT thresholding with experts to detect WMA was assessed using the individual equivalence index (γ), and an optimal threshold of the peak RSCT (RSCT*) that achieved maximum agreement was identified. RSCT* was then validated using the validation group, and the effect of AHA segment-specific thresholds was evaluated. Agreement was assessed using κ statistics. Results: The optimal threshold, RSCT* of -0.19, when applied to all AHA segments, led to high agreement (agreement rate = 92.17%, κ = 0.82) and interchangeability with experts (γ = -2.58%). The same RSCT* also achieved high agreement in the validation group (agreement rate = 90.29%, κ = 0.76, γ = -0.38%). The use of AHA segment-specific thresholds (range: 0.16 to -0.23 across AHA segments) slightly improved agreement (1.79% increase). Conclusion: RSCT thresholding was interchangeable with expert visual analysis in detecting segmental WMA from 4D CT and may be used as an objective decision classifier.Keywords: CT, Left Ventricle, Regional Endocardial Shortening, Wall Motion Abnormality Supplemental material is available for this article. © RSNA, 2023.

Transcatheter Hepatic Conduit-Azygous Vein Connection Reduces Pulmonary Arteriovenous Malformations in a Cyanotic Fontan Patient.

The authors report a closed-chest, transcatheter large-vessel connection (hepatic conduit to azygous vein) to reverse pulmonary arteriovenous malformations in a 10-year-old patient after Fontan for heterotaxy/interrupted inferior vena cava, with an increase in oxygen saturation from 78% to 96%. Computational fluid dynamics estimated a 14-fold increase in hepatic blood flow to the left pulmonary artery (from 1.3% to 14%). (Level of Difficulty: Advanced.).

Cardiovascular profile of contemporary treatments of renal cell carcinoma: A single-center prospective study.

BACKGROUND: Tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs) have revolutionized the treatment of metastatic renal cell carcinoma (mRCC). Emerging data suggest that these agents can result in clinically significant cardiotoxicity, compromising the care. METHODS: We conducted a prospective longitudinal study to evaluate the incidence of de novo cardiac dysfunction as assessed by echocardiography and blood biomarkers in mRCC patients receiving TKI with or without ICI followed at baseline, 3-month and 6-month. We recruited consecutive newly diagnosed mRCC patients treated at our institution between 2015 and 2018 as well as patients with localized RCC not treated with systemic therapies and healthy control (HC) subjects for comparison. RESULTS: Twenty-eight patients were enrolled in the mRCC group (a mean age of 65.2 ± 7.5 years), 29 patients in the localized RCC group (63.6 ± 8.9 years), and 20 volunteers in the HC group (52.9 ± 9.6 years). At baseline, patients from all three groups had normal cardiac function as measured by left ventricular ejection fraction (LVEF), although patients with mRCC or localized RCC had significantly lower mean LVEF compared to HC (61.9%, 62.4%, and 68.1% respectively). Otherwise, there were no statistically significant changes in echocardiographic parameters or incidence of clinical heart failure from baseline to 6-months in patients with mRCC. Cardiac blood biomarkers including troponin I, brain natriuretic peptide, and galectin-3 remained stable over time. CONCLUSION: Our findings suggest that contemporary treatment strategies of mRCC at this single institution are well tolerated without clinically meaningful overt declines in cardiac function over time. Further studies are warranted to include a larger number of patients to better assess the overall cardiovascular safety associated with contemporary treatments of mRCC.

Clinical Presentation and Outcomes of Kawasaki Disease in Children from Latin America: A Multicenter Observational Study from the REKAMLATINA Network.

OBJECTIVES: To describe the clinical presentation, management, and outcomes of Kawasaki disease (KD) in Latin America and to evaluate early prognostic indicators of coronary artery aneurysm (CAA). STUDY DESIGN: An observational KD registry-based study was conducted in 64 participating pediatric centers across 19 Latin American countries retrospectively between January 1, 2009, and December 31, 2013, and prospectively from June 1, 2014, to May 31, 2017. Demographic and initial clinical and laboratory data were collected. Logistic regression incorporating clinical factors and maximum coronary artery z-score at initial presentation (between 10 days before and 5 days after intravenous immunoglobulin [IVIG]) was used to develop a prognostic model for CAA during follow-up (>5 days after IVIG). RESULTS: Of 1853 patients with KD, delayed admission (>10 days after fever onset) occurred in 16%, 25% had incomplete KD, and 11% were resistant to IVIG. Among 671 subjects with reported coronary artery z-score during follow-up (median: 79 days; IQR: 36, 186), 21% had CAA, including 4% with giant aneurysms. A simple prognostic model utilizing only a maximum coronary artery z-score ≥2.5 at initial presentation was optimal to predict CAA during follow-up (area under the curve: 0.84; 95% CI: 0.80, 0.88). CONCLUSION: From our Latin American population, coronary artery z-score ≥2.5 at initial presentation was the most important prognostic factor preceding CAA during follow-up. These results highlight the importance of early echocardiography during the initial presentation of KD.

Cardiovascular toxicities with pediatric tyrosine kinase inhibitor therapy: An analysis of adverse events reported to the Food and Drug Administration.

We sought to examine cardiovascular toxicities associated with tyrosine kinase inhibitors in pediatrics. We examined 1624 pediatric adverse events with imatinib, dasatinib, sorafenib, pazopanib, crizotinib, and ruxolitinib reported to the Food and Drug Administration between January 1, 2015, and August 14, 2020. There were 102 cardiovascular event reports. Hypertension was the most commonly reported cardiovascular event and was most frequently associated with sorafenib and pazopanib. The presence of infection increased the reporting odds of cardiovascular events overall and specifically cardiac arrest, heart failure, and hypertension. These data provide early insight into cardiovascular toxicities with tyrosine kinase inhibitor use in pediatrics.

Detection of left ventricular wall motion abnormalities from volume rendering of 4DCT cardiac angiograms using deep learning.

Background: The presence of left ventricular (LV) wall motion abnormalities (WMA) is an independent indicator of adverse cardiovascular events in patients with cardiovascular diseases. We develop and evaluate the ability to detect cardiac wall motion abnormalities (WMA) from dynamic volume renderings (VR) of clinical 4D computed tomography (CT) angiograms using a deep learning (DL) framework. Methods: Three hundred forty-three ECG-gated cardiac 4DCT studies (age: 61 ± 15, 60.1% male) were retrospectively evaluated. Volume-rendering videos of the LV blood pool were generated from 6 different perspectives (i.e., six views corresponding to every 60-degree rotation around the LV long axis); resulting in 2058 unique videos. Ground-truth WMA classification for each video was performed by evaluating the extent of impaired regional shortening visible (measured in the original 4DCT data). DL classification of each video for the presence of WMA was performed by first extracting image features frame-by-frame using a pre-trained Inception network and then evaluating the set of features using a long short-term memory network. Data were split into 60% for 5-fold cross-validation and 40% for testing. Results: Volume rendering videos represent ~800-fold data compression of the 4DCT volumes. Per-video DL classification performance was high for both cross-validation (accuracy = 93.1%, sensitivity = 90.0% and specificity = 95.1%, κ: 0.86) and testing (90.9, 90.2, and 91.4% respectively, κ: 0.81). Per-study performance was also high (cross-validation: 93.7, 93.5, 93.8%, κ: 0.87; testing: 93.5, 91.9, 94.7%, κ: 0.87). By re-binning per-video results into the 6 regional views of the LV we showed DL was accurate (mean accuracy = 93.1 and 90.9% for cross-validation and testing cohort, respectively) for every region. DL classification strongly agreed (accuracy = 91.0%, κ: 0.81) with expert visual assessment. Conclusions: Dynamic volume rendering of the LV blood pool combined with DL classification can accurately detect regional WMA from cardiac CT.

Fitbit Use and Activity Levels From Intervention to 2 Years After: Secondary Analysis of a Randomized Controlled Trial.

BACKGROUND: There has been a rapid increase in the use of commercially available activity trackers, such as Fitbit, in physical activity intervention research. However, little is known about the long-term sustained use of trackers and behavior change after short-term interventions. OBJECTIVE: This study aims to use minute-level data collected from a Fitbit tracker for up to 2 years after the end of a randomized controlled trial to examine patterns of Fitbit use and activity over time. METHODS: Participants in this secondary data analysis were 75 female breast cancer survivors who had been enrolled in a 12-week physical activity randomized controlled trial. Participants randomized to the exercise intervention (full intervention arm) received a Fitbit One, which was worn daily throughout the 12-week intervention, and then were followed for 2 years after the intervention. Participants randomized to the waitlist arm, after completing the randomized controlled trial, received a Fitbit One and a minimal version of the exercise intervention (light intervention arm), and then were followed for 2 years after the intervention. Average and daily adherence and MVPA were compared between the 2 groups in the interventional and postinterventional periods using both linear and generalized additive mixed effects models. RESULTS: Adherence to wearing the Fitbit during the 12-week intervention period was significantly higher in the full intervention arm than in the light intervention arm (85% vs 60%; P<.001). Average adherence was significantly lower for both study arms during the follow-up period than in the intervention period; however, there were statistically different patterns of adherence during the follow-up period, with the light intervention arm having steeper declines than the full intervention arm over time (P<.001). Similar to the adherence results, mean minutes of Fitbit-measured MVPA was higher for the full intervention arm than for the light intervention arm during the 12-week intervention period (mean MVPA 27.89 minutes/day, SD 16.38 minutes/day vs 18.35 minutes/day, SD 12.64 minutes/day; P<.001). During the follow-up period, average MVPA was significantly lower than the 12-week intervention period for both the full intervention arm (21.74 minutes/day, SD 24.65 minutes/day; P=.002) and the light intervention arm (15.03 minutes/day, SD 13.27 minutes/day; P=.004). Although the mean MVPA in each arm was similar across the follow-up period (P=.33), the pattern of daily MVPA was significantly different between the 2 groups (P<.001). CONCLUSIONS: While adherence to wearing activity trackers and maintaining physical activities declined after completion of a 12-week exercise intervention, a more active interventional strategy resulted in greater wear time and activity levels during the intervention and more stable patterns of adherence and activity in the long term. An improved understanding of long-term maintenance patterns may inform improved exercise interventions that result in sustained increases in physical activity. TRIAL REGISTRATION: ClinicalTrials.gov NCT02332876; https://clinicaltrials.gov/ct2/show/NCT02332876.

Deep learning automates detection of wall motion abnormalities via measurement of longitudinal strain from ECG-gated CT images.

Introduction: 4D cardiac CT (cineCT) is increasingly used to evaluate cardiac dynamics. While echocardiography and CMR have demonstrated the utility of longitudinal strain (LS) measures, measuring LS from cineCT currently requires reformatting the 4D dataset into long-axis imaging planes and delineating the endocardial boundary across time. In this work, we demonstrate the ability of a recently published deep learning framework to automatically and accurately measure LS for detection of wall motion abnormalities (WMA). Methods: One hundred clinical cineCT studies were evaluated by three experienced cardiac CT readers to identify whether each AHA segment had a WMA. Fifty cases were used for method development and an independent group of 50 were used for testing. A previously developed convolutional neural network was used to automatically segment the LV bloodpool and to define the 2, 3, and 4 CH long-axis imaging planes. LS was measured as the perimeter of the bloodpool for each long-axis plane. Two smoothing approaches were developed to avoid artifacts due to papillary muscle insertion and texture of the endocardial surface. The impact of the smoothing was evaluated by comparison of LS estimates to LV ejection fraction and the fractional area change of the corresponding view. Results: The automated, DL approach successfully analyzed 48/50 patients in the training cohort and 47/50 in the testing cohort. The optimal LS cutoff for identification of WMA was -21.8, -15.4, and -16.6% for the 2-, 3-, and 4-CH views in the training cohort. This led to correct labeling of 85, 85, and 83% of 2-, 3-, and 4-CH views, respectively, in the testing cohort. Per-study accuracy was 83% (84% sensitivity and 82% specificity). Smoothing significantly improved agreement between LS and fractional area change (R 2: 2 CH = 0.38 vs. 0.89 vs. 0.92). Conclusion: Automated LV blood pool segmentation and long-axis plane delineation via deep learning enables automatic LS assessment. LS values accurately identify regional wall motion abnormalities and may be used to complement standard visual assessments.

Minimizing cardiac toxicity in children with acute myeloid leukemia.

Anthracycline chemotherapy remains an integral component of modern pediatric acute myeloid leukemia (AML) regimens and is often delivered at high doses to maximize cancer survival. Unfortunately, high-dose anthracyclines are associated with a significant risk of cardiotoxicity, which may result in early and/or long-term left ventricular systolic dysfunction and heart failure. Moreover, the development of cardiotoxicity during pediatric AML therapy is associated with lower event-free and overall survival, which may be partially attributable to incomplete anthracycline delivery. A combined strategy of primary cardioprotection and close cardiac monitoring can maximize chemotherapy delivery while reducing the toxicity of intensive AML therapy. Primary cardioprotection using dexrazoxane reduces short-term cardiotoxicity without compromising cancer survival. Liposomal anthracycline formulations, which are under active investigation, have the potential to mitigate cardiotoxicity while also improving antitumor efficacy. Primary cardioprotective strategies may reduce but not eliminate the risk of cardiotoxicity; therefore, close cardiac monitoring is also needed. Standard cardiac monitoring consists of serial echocardiographic assessments for left ventricular ejection fraction decline. Global longitudinal strain has prognostic utility in cancer therapy-related cardiotoxicity and may be used as an adjunct assessment. Additional cardioprotective measures should be considered in response to significant cardiotoxicity; these include cardiac remodeling medications to support cardiac recovery and anthracycline dose interruption and/or regimen modifications. However, the withholding of anthracyclines should be limited to avoid compromising cancer survival. A careful approach to cardioprotection during AML therapy is critical to maximize the efficacy of leukemia treatment while minimizing the short- and long-term risks of cardiotoxicity.

Molecular mechanisms of anthracycline cardiovascular toxicity.

Anthracyclines are effective chemotherapeutic agents, commonly used in the treatment of a variety of hematologic malignancies and solid tumors. However, their use is associated with a significant risk of cardiovascular toxicities and may result in cardiomyopathy and heart failure. Cardiomyocyte toxicity occurs via multiple molecular mechanisms, including topoisomerase II-mediated DNA double-strand breaks and reactive oxygen species (ROS) formation via effects on the mitochondrial electron transport chain, NADPH oxidases (NOXs), and nitric oxide synthases (NOSs). Excess ROS may cause mitochondrial dysfunction, endoplasmic reticulum stress, calcium release, and DNA damage, which may result in cardiomyocyte dysfunction or cell death. These pathophysiologic mechanisms cause tissue-level manifestations, including characteristic histopathologic changes (myocyte vacuolization, myofibrillar loss, and cell death), atrophy and fibrosis, and organ-level manifestations including cardiac contractile dysfunction and vascular dysfunction. In addition, these mechanisms are relevant to current and emerging strategies to diagnose, prevent, and treat anthracycline-induced cardiomyopathy. This review details the established and emerging data regarding the molecular mechanisms of anthracycline-induced cardiovascular toxicity.

Left ventricular segmental strain and the prediction of cancer therapy-related cardiac dysfunction.

AIMS: We aimed to determine the early changes and predictive value of left ventricular (LV) segmental strain measures in women with breast cancer receiving doxorubicin. METHODS AND RESULTS: In a cohort of 237 women with breast cancer receiving doxorubicin with or without trastuzumab, 1151 echocardiograms were prospectively acquired over a median (Q1-Q3) of 7 (2-24) months. LV ejection fraction (LVEF) and 36 segmental strain measures were core lab quantified. A supervised machine learning (ML) model was then developed using random forest regression to identify segmental strain measures predictive of nadir LVEF post-doxorubicin completion. Cancer therapy-related cardiac dysfunction (CTRCD) was defined as a ≥10% absolute LVEF decline pre-treatment to a value <50%. Median (Q1-Q3) baseline age was 48 (41-57) years. Thirty-five women developed CTRCD, and eight of these developed symptomatic heart failure. From pre-treatment to doxorubicin completion, longitudinal strain worsened across the basal and mid-LV segments but not in the apical segments; circumferential strain worsened primarily in the septum; radial strain worsened uniformly and transverse strain remained unchanged across all LV segments. In the ML model, anterolateral and inferoseptal circumferential strain were the most predictive features; longitudinal and transverse strain in the basal inferoseptal, anterior, basal anterolateral, and apical lateral segments were also top predictive features. The addition of predictive segmental strain measures to a model including age, cancer therapy regimen, hypertension, and LVEF increased the area under the curve (AUC) from 0.70 (95% confidence interval (CI) 0.60-0.80) to 0.87 (95% CI 0.81-0.92), ΔAUC = 0.18 (95% CI 0.08-0.27) for the prediction of CTRCD. CONCLUSION: Our findings suggest that segmental strain measures can enhance cardiotoxicity risk prediction in women with breast cancer receiving doxorubicin.