BACKGROUND:Thoracic radiotherapy (RT) results in pulmonary fibrosis that has been hypothesised to increase the risk of pulmonary hypertension (PH); however, dose effects to cardiopulmonary structures predicting PH have not been systematically studied. METHODS:Multi-institutional retrospective cohort analysis of patients with non-small cell lung cancer treated with thoracic RT. The pulmonary arteries (PA), distal pulmonary vasculature, lungs and heart were segmented. Radiotherapy dose parameters (mean, maximum and volume (V) receiving X Gy in 5 Gy increments) were extracted. Area under the receiver operating curve (AUROC) analyses estimating PH and Fine-Gray regressions were performed. RESULTS:Of 848 patients included (n=746 discovery; n=102 validation), 49.9% were women and the median age was 65 years (IQR, 58-73 years). The 2-year cumulative incidence of PH was 11.6%. PA V10 Gy demonstrated the highest AUROC for predicting PH (0.58) and was significantly associated with the risk of PH on multivariable regression adjusting for cardiopulmonary risk factors in the discovery (subdistribution HR (sHR) 1.01; 95% CI 1.00 to 1.02; p=0.013) and validation (sHR 1.03, 95% CI 1.00 to 1.05; p=0.019) cohorts. In those who developed PH after RT (vs PH-negative), moderate or greater tricuspid disease and right ventricular systolic dysfunction (RVSD) were more common (18.7% vs 0.2% (p<0.001) and 3.3% vs 0.2% (p=0.003), respectively). CONCLUSIONS:PH was common following thoracic RT and associated with PA radiation dose. Patients with PH were more likely to harbour tricuspid disease and RVSD. These hypothesis-generating findings are suggestive that PH following thoracic RT may occur through a pathophysiological process distinct from RT-induced pulmonary fibrosis.

Importance Breast cancer is the most common cancer diagnosed in women. Therapies for breast cancer are evolving rapidly, and several are associated with cardiovascular adverse effects, can exacerbate cardiovascular risk factors, or can increase the risk of cardiovascular disease. Observations Advances in screening and treatment have led to earlier diagnosis and improved disease-free survival. For long-term survivors of breast cancer, cardiovascular adverse effects can pose a greater threat to overall long-term health than the cancer itself. Additionally, the increasing incidence of breast cancer in younger, premenopausal women has created a distinct demographic with unique medical needs. Conclusions and Relevance Cardiology practitioners need to remain updated on rapidly evolving breast cancer therapies to care for this growing, unique patient population. The field of cardio-oncology has evolved to address the cardiovascular needs of patients and survivors.

BACKGROUND:Although some cancer immunotherapies have been linked to increased cardiovascular risk, data on T-cell engager (TCE) therapy-associated cardiovascular complications remain limited. OBJECTIVES:This study sought to characterize the incidence and factors associated with cardiovascular events (CVEs) and mortality during TCE therapy. METHODS:We conducted a dual-center retrospective study of patients with cancer treated with TCEs between 2016 and 2024. The cumulative incidence of on-treatment CVEs (heart failure, arrhythmias, myocardial infarction, stroke) and cardiovascular mortality was evaluated using Fine-Gray competing-risks models incorporating time-dependent grade ≥2 cytokine-release syndrome (CRS) and/or immune effector cell-associated neurotoxicity syndrome (ICANS). Factors associated with all-cause mortality were assessed using Cox models including CVEs as a time-dependent covariate. RESULTS:Among 567 patients (median age 67 years [Q1-Q3: 57-75]; 46.0% female), 25.9% had preexisting cardiovascular disease. The most common malignancies were multiple myeloma (40.9%) and acute lymphoblastic leukemia (35.6%). The restricted mean follow-up was 248 days (range: 0-973), during which 65 CVEs occurred (cumulative incidence 10.4%; 95% CI: 8.1-13.1), most commonly new left ventricular dysfunction (2.3%) and new-onset atrial fibrillation (2.1%). Cardiovascular mortality was rare (2 cases, 0.4%). Coronary artery disease was the only baseline variable independently associated with CVEs, whereas development of grade ≥2 CRS and/or ICANS was associated with a significant time-dependent increase in CVE risk. CVEs were significantly associated with higher all-cause mortality, independent of baseline clinical factors and TCE agent. CONCLUSIONS:TCE therapy demonstrates a favorable cardiovascular safety profile overall, yet cardiovascular complications during therapy are associated with markedly increased mortality risk. Patients with preexisting coronary artery disease and those who develop high-grade CRS and/or ICANS represent high-risk groups that may benefit from intensified cardiovascular assessment and monitoring.

BACKGROUND:Contemporary trends in pulmonary embolism (PE)-attributable mortality among U.S. patients with heart failure (HF) remain underexplored. OBJECTIVES:The objective of the study was to evaluate trends in PE-attributable mortality from 2010 to 2020 among US patients with HF, stratified by age, sex, race/ethnicity, urbanicity, and region. METHODS:Data on PE-attributable mortality in HF patients aged ≥25 years were obtained from the Centers for Disease Control and Prevention Wide-Ranging Online Data for Epidemiologic Research database from January 2010 to December 2020. Age-adjusted mortality rates (AAMRs) were analyzed using joinpoint regression to calculate average annual percentage change with 95% CIs. Concurrent trends in HF prevalence and venous thromboembolism risk factors were assessed using the National Health and Nutrition Examination Survey data set. RESULTS:Between 2010 and 2020, 38,129 U.S. patients with HF aged ≥25 years (17,772 men and 20,357 women) died from PE, corresponding to a proportionate mortality of 97.5 per 1,000 deaths (≈9.8%). AAMR linearly increased during this period (average annual percentage change: +4.7%; 95% CI: 3.3%-6.1%; P < 0.001), with no sex differences (P for parallelism = 0.23). The AAMR increased among individuals aged 25 to 65 years, Asian/Pacific Islanders, non-Hispanic/non-Latinx Black individuals, and residents of the Midwest. Although age-adjusted prevalence of HF plateaued overall, HF patients aged with concomitant rises in age-adjusted rates of obesity, prior smoking, atherosclerotic cardiovascular disease, chronic kidney disease, and cancer (P < 0.001 for all). CONCLUSIONS:PE-attributable mortality among U.S. patients with HF has risen significantly over the past decade particularly among younger adults, certain ethnoracial groups, and residents of the Midwest.

e13581 Background: Cardiovascular disease (CVD) is a leading cause of death among prostate cancer (PC) survivors, and treatment with androgen deprivation therapy (ADT) negatively impacts metabolic factors and CVD risk. A standardized approach to delivering patient education regarding CVD risk remains a major unmet need. To address this, we implemented CV CARE (CardioVascular Care of Androgen Related Effects) to assess the feasibility of delivering advanced practice provider (APP)-driven personalized CV risk assessment and patient education in an oncology clinic at ADT initiation. Methods: Patients with PC receiving ≥ 24 weeks of ADT were enrolled in a DFCI IRB approved study within 12 weeks of starting ADT. CV risk labs (lipid panel, HbgA1c) were collected at enrollment, and patients received education from APPs at study start and 24 weeks later. Atherosclerotic Cardiovascular Disease (ASCVD) risk scores were calculated to determine personalized CVD risk, and the ABCDE (Awareness, Blood pressure, Cholesterol/Cigarette cessation, Diabetes/Diet, and Exercise) algorithm was used to educate on reversible CVD risk factors. Patients identified as high risk (ASCVD score of > 20%) were referred to cardio-oncology. Lipid levels, HgbA1c, ASCVD risk, and ADT effects were communicated via electronic medical record to patients’ care teams. Following study completion, patients and APPs were interviewed to provide feedback that will be used to revise the program. The primary endpoint is the feasibility of integrating the revised CV CARE program into the clinic workflow, as determined by continued participation rates (if ≥75% of patients remain in the program at week 24). Secondary endpoints include medication changes between ADT initiation and week 24, and clinician and patient reported satisfaction. Results: In total, 60 patients were enrolled into CV CARE (Table 1). 43.3% (26) completed the study, and 26.7% (16) remain in follow-up. Qualitative interviews assessing clinician and patient satisfaction with CV CARE are ongoing. Conclusions: We have completed enrollment in a study to explore the feasibility of integrating APP-delivered CVD risk assessment, patient education, and standardized multi-disciplinary communication for PC patients starting ADT. Ongoing assessments include feasibility, clinician and patient satisfaction, and changes in CVD-associated medications. This study was approved and funded by the National Comprehensive Cancer Network (NCCN) Oncology Research Program (ORP) from general research support provided by Pfizer Inc. and Sumitomo Pharma America, Inc. Clinical trial information: NCT06202820 . Baseline patient characteristics. Characteristics Overall N=60 (%) Age, Median, IQR 69 (64-73) Ethnicity (non-Hispanic) 95% (57) Localized Disease 70% (42) Current or Former Smoker 30% (18) Patients on Anti-HTN Medication 58.3% (35) Patients on Statin Medication 61.7% (37) Hypertension 71.7% (43) Hyperlipidemia 70% (42) Diabetes 20% (12)

Importance:The introduction of immune checkpoint inhibitor (ICI) therapy has improved cancer outcomes but at the cost of adverse events, mainly related to the immune system. Cardiovascular (CV) toxic effects, and especially myocarditis, are of particular concern and are the subject of this position statement by the International Cardio-Oncology Society with representation of experts from oncology, hematology, and cardiology. Observations:CV toxic effects of ICI therapies include inflammation-associated diseases, such as myocarditis, pericarditis, and vasculitis, as well as the aggravation of chronic inflammatory conditions, such as atherosclerosis with acute ischemic complications (myocardial infarction and stroke). Patients taking ICI therapies can also develop cardiac dysfunction, stress-induced cardiomyopathy (Takotsubo or apical ballooning syndrome), and heart failure without inflammatory cell infiltration of the myocardium. Atrial and ventricular arrhythmias can emerge in the setting of a systemic inflammatory milieu, myocarditis, or ischemia. Of all potential CV adverse effects, myocarditis remains of highest concern, although fatality rates have declined over time with a broadening spectrum of presentations ranging from troponin elevation of uncertain significance to smoldering, nonsevere, and severe or fulminant myocarditis. Conclusions and Relevance:Concerns for myocarditis continue to dominate the spectrum of CV toxic effects in patients receiving ICI therapy. Recommendations for management vary according to severity. Multidisciplinary collaborations remain key for managing acute toxic effects and future cancer treatment decisions, including ICI rechallenge. Ischemic heart disease constitutes the main differential diagnosis in these patients, while pericarditis can be concomitantly present, and atrial and ventricular arrhythmias can also complicate the clinical picture. Several gaps in knowledge are identified and require further research.

BACKGROUND AND AIMS:Immune checkpoint inhibitors (ICI) are associated with life-threatening myocarditis but milder presentations are increasingly recognized. The same autoimmune process that causes ICI myocarditis can manifest concurrent generalized myositis, myasthenia-like syndrome, and respiratory muscle failure. Prognostic factors for this 'cardiomyotoxicity' are lacking. The main aim of this study was to determine predictors and construct a risk score associated with negative outcomes in patients admitted for ICI myocarditis. METHODS:A multicentre registry collected data retrospectively from 17 countries between 2014 and 2023. A multivariable Cox regression model was used to determine risk factors for the primary composite outcome: time to severe arrhythmia, heart failure, respiratory muscle failure, and/or cardiomyotoxicity-related death. Covariates included demographics, comorbidities, cardiomuscular symptoms, diagnostics, and treatments. Time-dependent covariates were used, and missing data were imputed. A point-based prognostic risk score was derived and externally validated. RESULTS:In 748 patients (67% male, age 23-94 years), 30-day incidence of the primary composite outcome, cardiomyotoxic death, and overall death were 33%, 13%, and 17%, respectively. By multivariable analysis, the primary composite outcome was associated with active thymoma (hazard ratio [HR] 3.6, 95% confidence interval [CI] 1.7-7.7), presence of cardiomuscular symptoms (HR 2.6 [1.5-4.2]), low QRS voltage on presenting electrocardiogram (HR for ≤0.5 mV vs >1 mV 1.9 [1.1-3.1]), left ventricular ejection fraction (LVEF) < 50% (HR 1.7 [1.1-2.6]), and incremental troponin elevation (HR 1.8 [1.4-2.4], 2.9 [1.8-4.7], and 4.6 [2.3-9.3], for 20, 200, and 2000-fold above upper reference limit, respectively). A prognostic risk score developed using these parameters showed good performance; 30-day primary outcome incidence increased gradually from 4% (risk score = 0) to 81% (risk score ≥ 4). This risk score was externally validated in two independent French and US cohorts. This risk score was used prospectively in the external French cohort to identify low-risk patients who were managed with no immunosuppression resulting in no cardiomyotoxic events. CONCLUSIONS:ICI-associated myocarditis can manifest with high morbidity and mortality. Myocarditis severity is associated with magnitude of troponin, thymoma, low QRS voltage, depressed LVEF, and cardiomuscular symptoms. A risk score incorporating these features performed well. CLINICAL TRIAL REGISTRATION:NCT04294771 and NCT05454527.

The introduction of immune checkpoint inhibitor (ICI) therapy has improved cancer outcomes but at the cost of adverse events, mainly related to the immune system. Cardiovascular (CV) toxic effects, and especially myocarditis, are of particular concern and are the subject of this position statement by the International Cardio-Oncology Society with representation of experts from oncology, hematology, and cardiology. CV toxic effects of ICI therapies include inflammation-associated diseases, such as myocarditis, pericarditis, and vasculitis, as well as the aggravation of chronic inflammatory conditions, such as atherosclerosis with acute ischemic complications (myocardial infarction and stroke). Patients taking ICI therapies can also develop cardiac dysfunction, stress-induced cardiomyopathy (Takotsubo or apical ballooning syndrome), and heart failure without inflammatory cell infiltration of the myocardium. Atrial and ventricular arrhythmias can emerge in the setting of a systemic inflammatory milieu, myocarditis, or ischemia. Of all potential CV adverse effects, myocarditis remains of highest concern, although fatality rates have declined over time with a broadening spectrum of presentations ranging from troponin elevation of uncertain significance to smoldering, nonsevere, and severe or fulminant myocarditis. Concerns for myocarditis continue to dominate the spectrum of CV toxic effects in patients receiving ICI therapy. Recommendations for management vary according to severity. Multidisciplinary collaborations remain key for managing acute toxic effects and future cancer treatment decisions, including ICI rechallenge. Ischemic heart disease constitutes the main differential diagnosis in these patients, while pericarditis can be concomitantly present, and atrial and ventricular arrhythmias can also complicate the clinical picture. Several gaps in knowledge are identified and require further research.

Background Testicular cancer is the most common malignancy in young men, and cisplatin-based chemotherapy provides excellent long-term survival. However, cisplatin-associated cardiovascular toxicity spans a broad spectrum, and evidence guiding rechallenge after an acute coronary event is limited. Case Summary A 24-year-old man with testicular cancer and no cardiovascular risk factors developed chest pain and elevated troponins early in his cisplatin therapy. Coronary angiography revealed a nonocclusive left anterior descending artery thrombus. After treatment with antiplatelet and anticoagulant therapy, the thrombus resolved, and he subsequently underwent a carefully monitored cisplatin rechallenge. Discussion Given cisplatin's curative benefit, a multidisciplinary team—including cardiology, oncology, and pharmacy—assessed the risks and benefits of continuing therapy. With close surveillance and optimized medical management, including anti-ischemic therapy and anticoagulation, cisplatin was safely reintroduced. Take-Home Messages Cisplatin-induced myocardial infarction requires prompt recognition and coordinated care. With multidisciplinary evaluation, rechallenge can be safely performed in select patients.

Objective: Patients with cancer who receive radiation therapy to the thorax often develop radiation-induced heart disease (RIHD) decades later. Previous chest radiation is associated with elevated perioperative risk of complications and mortality after cardiac surgery. Whether the type of valve (mechanical vs bioprosthetic) used affects outcomes in patients with RIHD is unknown. Methods: This retrospective review analyzed the characteristics and postoperative outcomes of patients with a previous history of chest radiation for Hodgkin or non-Hodgkin lymphoma who underwent surgical valve replacement at a single institution between 2000 and 2021. Both 30-day perioperative outcomes and long-term survival were assessed. Results: Patients who received mechanical valve tended to be younger, have more valves replaced, and have undergone previous coronary artery bypass grafting than bioprosthetic valve recipients. Valve type alone did not alter perioperative complications or overall survival. Median survival was 11.0 years in mechanical and 10.9 years in bioprosthetic valve patients (P 1/4 .930). Twelve patients underwent valve reinterventions (6 mechanical, 6 bioprosthetic), and 3 underwent transplant. Single-valve (aortic valve or mitral valve) recipients fared better with median survival of 13.3 years compared with 6.2 years in those who underwent combined aortic valve replacement plus mitral valve replacement (P < .0001). Conclusions: Patients with RIHD who undergo surgical valve replacement have similarly suboptimal short- and long-term outcomes regardless of mechanical versus bioprosthetic valve type. Those who required combined aortic and mitral valve replacement had especially high 10-year overall mortality. Further investigation in a larger dataset including transcatheter approaches is warranted.

Background:The independent effects of social and environmental factors on asthma and chronic obstructive pulmonary disease (COPD) are well-documented, but less is known about their combined impact across US neighborhoods. This study aimed to determine the combined and individual associations of neighborhood-level social vulnerability and environmental burden with the prevalence of asthma and COPD. Methods:This cross-sectional study analyzed 71,677 US census tracts, linking the 2022 CDC Environmental Justice Index (EJI) rankings and its subcomponents (environmental burden module [EBM] and social vulnerability module [SVM]) to the 2023 CDC PLACES dataset. Multivariable quasi-Poisson regression with an offset function was used to compare covariate-adjusted risk ratios of health indicators across quartiles of neighborhood socio-environmental burden. Findings:Among the 71,677 neighborhoods studied, the median proportion of females was 50.90%. The median proportions of individuals aged 18 to 44, 45 to 64, and ≥65 were 30.6%, 26.7%, and 15.3%, respectively, with 22.6% of the Hispanic population. Asthma and COPD prevalence rates increased with increasing EJI and EBM quartiles. Neighborhoods with the highest socio-environmental burden (Q4 EJI) had significantly higher rates of asthma (RR:1.102, 95% CI: 1.087-1.117, p < 0.001) and COPD (RR:1.156, 95% CI:1.141-1.172, p < 0.001) compared to neighborhoods with the lowest burden (Q1 EJI), after adjusting for covariates. Similarly, neighborhoods with the highest environmental burden (Q4 EBM) had higher rates of asthma (RR: 1.091, 95% CI: 1.064-1.118, p < 0.001) and COPD (RR:1.099, 95% CI: 1.070-1.129, p < 0.001) compared with Q1 EBM, after adjusting for SVM and other covariates. Interpretation:A higher prevalence of obstructive lung disease is associated with neighborhoods experiencing high cumulative socio-environmental burden. Environmental burden showed an independent association with asthma and COPD prevalence, even after adjusting for social vulnerability and other factors. Funding:None.

Anthracycline and anthraquinone agents are major contributors to cancer therapy-related cardiac dysfunction in childhood cancer. However, evidence-based equivalence ratios for estimating individual risk have not been incorporated into international surveillance guidelines. The International Late Effects of Childhood Cancer Guideline Harmonization Group systematically reviewed the literature on equivalence ratios for doxorubicin, daunorubicin, epirubicin, idarubicin, and mitoxantrone. Based on available evidence, benefit-harm considerations, and expert consensus, the panel concluded that the risk of cardiac dysfunction is lower with daunorubicin and higher with mitoxantrone compared with doxorubicin (moderate-quality evidence; strong recommendation). The panel recommends using an approximate ratio of 0.6 to convert daunorubicin to a doxorubicin-equivalent dose and a ratio of 10.5 for mitoxantrone (low-quality evidence; moderate recommendation). No recommendation was made for epirubicin or idarubicin due to inconclusive evidence.

Introduction:Patients receiving thoracic radiotherapy (RT) have an increased risk of major adverse cardiac events (MACE) posttreatment. We utilized machine learning (ML) to discover novel predictors of MACE and validated them on an external cohort. Methods:This multi-institutional retrospective study included 984 patients [n = 803 non-small cell lung cancer (NSCLC), n = 181 breast cancer] treated with radiotherapy. Extreme gradient boosting was utilized to discover novel clinical, dosimetric, and anatomical features (CT-based cardiac substructure segmentations) associated with MACE in a cohort of locally advanced NSCLC patients. Fine-Gray regression was performed with non-cardiac death as a competing risk. External validation was performed utilizing independent cohorts of NSCLC or breast cancer patients. Results:In the discovery dataset (n = 701), 70 patients experienced MACE. ML modeling (training AUC, 0.68; testing AUC, 0.71) identified right and left atrial volume indices (RAVI and LAVI, respectively) as top predictors. After adjusting for baseline cardiovascular risk and known radiotherapy predictive factors, RAVI was associated with an increased risk of MACE [subdistribution hazard ratio (sHR) 1.02/unit, 95% confidence interval (CI): 1.00-1.04; p = 0.03]. In the validation cohorts (n = 102 NSCLC; n = 181 breast cancer), RAVI was associated with an increased risk of MACE (NSCLC: sHR 1.05, 95% CI: 1.001-1.106, p = 0.04; breast cancer: sHR 1.06, 95% CI: 1.01-1.11, p = 0.03). Similar findings were found for LAVI. Discussion:ML modeling identified right and left atrial enlargement as novel radiographic predictors for increased risk of MACE following chest radiotherapy, which was validated in independent breast and lung cancer datasets. Given that echocardiography studies have demonstrated the prognostic utility of atrial volume indices across cardiovascular risk groups, these findings warrant further study to identify additional strategies for upfront cardiovascular risk profiling.