Although Doxorubicin (Dox) is an effective anticancer drug, it can cause severe cardiotoxicity. While several mechanisms have been proposed to explain Dox-induced cardiomyopathy (DIC), strategies to prevent it remain limited. In previous research on isolated cardiomyocytes, we identified that Empagliflozin (EMPA), an antidiabetic drug, mitigated Dox-induced ER stress and apoptosis. In this in vivo study using rats, we further investigated EMPA's potential in preventing and treating DIC. Rats administered a cumulative dose of 15 mg/kg Dox exhibited significant cardiovascular damage, including left ventricular cavity dilation, decreased left ventricular ejection fraction (LVEF), ER dilation, mitochondrial defects and vacuole formation. These structural changes were linked to the activation of ER-stress pathways (PERK, IRE1 and ATF6) and upregulation of apoptotic proteins initiated by ER stress. When EMPA (10 mg/kg/day) was administered either prophylactically or concurrently with Dox, it significantly attenuated adverse LV remodelling and preserved LVEF. Additionally, EMPA prevented ER stress and subsequent apoptosis in the myocardium of the Dox + EMPA-treated group. These findings suggest that EMPA offers cardioprotective benefits in DIC, likely through the inhibition of ER-stress-induced myocardial injury.

Artificial intelligence (AI) offers new opportunities in cardio-oncology for early detection, risk stratification, and personalized management of cardiovascular complications in cancer patients. By leveraging data from electronic health records, blood biomarkers, imaging tests such as echocardiography, electrocardiograms, and wearables, AI models can facilitate prediction, detection and response to treatment of cardiovascular disease entities, pre-existing and developing as a consequence of cancer therapy. Specific to the latter, referred to as cardiotoxicity, widespread adoption has been hindered by the limited availability of large datasets for model training, insufficient external validation, and challenges in integrating AI tools into routine clinical workflows. Future progress will depend on advancements in AI technologies, rigorous multi-center validation, development of explainable models, and seamless integration into clinical practice. Barriers, not only from a systems perspective, but also from a provider and most importantly from a patient perspective will need to be addressed for successful implementation. With a broad multidisciplinary perspective and patient focus, AI can advance cardio-oncology care and improve outcomes for patients with cancer.

Cancer is a leading cause of death worldwide, though new therapies have increased patient survival. These therapies, however, have also raised concerns for cardiovascular toxicities, such as cardiomyopathies, coronary artery disease, hypertension and arrhythmias. Pulmonary arterial hypertension (PAH) is a rare condition that carries a poor prognosis and is often diagnosed at an advanced stage. The annual incidence in the general population is estimated to be between 1 and 2 cases per million. The highest prevalence occurs during the third and fourth decades of life; however, there are cases whose are identified after the sixth decade. It has increasingly become evident that various cancer therapies can exacerbate pulmonary hypertension, significantly impacting patient prognosis. It is recognized that oncologic treatments can cause endothelial dysfunction, including the pulmonary vasculature, and can have thrombotic effects, worsening PAH in patients with this disease. The objective of this study is to describe our experience with patients with a concomitant diagnosis of PAH and cancer, who received prostanoid therapy to be able to complete specific cancer treatments. The PULmonary Artery HYpertension and Cancer (PULAHYCA) pilot study is an observational study of patients with a cancer diagnosis planning to initiate a specific oncologic treatment, with PAH detected during baseline assessment. Patients with PAH due to group 1and group 4 were included, defined as per the 2022 European Society of Cardiology (ESC) guidelines, that require a mean pulmonary artery pressure (mPAP) greater than 20 mm Hg at rest, increased pulmonary artery resistance of more than 2 Wood units and wedge pressure less than 15 mm Hg. The PAH risk category was established according to the ESC guidelines and the REVEAL Lite 2 score. Patients with an intermediate risk with a diagnosis of more than 6 months were included. After screening 349 PH patients, 12 patients were included in the study. All participants had a normal ejection fraction and were treated with a combination of a 5- phosphodiesterase inhibitor, an endothelin receptor antagonist, and treprostinil. Eight patients were classified under group 1 pulmonary hypertension, and four under group 4 pulmonary hypertension. During the 12-month follow-up, patients demonstrated significant clinical and hemodynamic improvement. Functional capacity, measured by the six-minute walk test (6MWT), increased significantly from 325 [304–440] meters at baseline to 401 [315–455] meters at 12 months (p = 0.0014). B-type natriuretic peptide (BNP) levels decreased notably from 321 [205–506] pg/ml to 188 [100–229] pg/ml (p = 0.0001). Pulmonary vascular resistance (PVR) also showed a significant reduction, from 3.8 [3.3–4.2] Woods Units (WU) to 3.5[2.5–3.7] WU (p = 0.00018). All patients survived during the study period and could complete their cancer treatment, which included. The PULAHYCA PILOT study demonstrates that treatment with subcutaneous Treprostinil in intermediate-risk PH patients undergoing initial oncologic therapy enables completion of cancer treatment, leading to either remission or chronic disease control. Furthermore, beyond the oncologic benefit, patients exhibited improvements in both clinical status and objective markers of pulmonary hypertension severity.

Toxicities from CAR-T cell therapy are complex, severe, and often require multidisciplinary management. To standardize care, our institution established a Serious Adverse Event Oversight Committee (SAEOC), comprising specialists from hematology, neurology, nephrology, infectious diseases, intensive care, cardiology, and pharmacy. Once activated, the committee convenes virtually twice daily until SAE resolution or deactivation. We retrospectively examined outcomes in patients with macrophage activation syndrome/ hemophagocytic lymphohistiocytosis (MAS/HLH) treated before and after SAEOC implementation in December 2022. Provider perceptions were evaluated through a survey.The SAEOC was activated for 19 patients, most frequently for MAS-like syndromes (n=7), MAS/HLH (n=4), and high-grade ICANS (n=14). Additional triggers included CD8+ T-cell lymphoproliferative disorder, delayed IEC neurotoxicity and enterocolitis, massive pulmonary embolism, and diffuse alveolar hemorrhage.To assess outcomes, we focused on a more homogeneous subgroup of patients with MAS/HLH, comparing all patients treated prior to SAEOC implementation (n=8; 3 axi-cel, 1 tisa-cel, 1 ide-cel, 1 cilta-cel, 2 investigational CAR-Ts) with those treated after (n=6; 3 axi-cel, 1 brexu-cel, 2 cilta-cel). In the post-SAEOC cohort, 30- and 100-day treatment-related mortality were numerically lower, compared with the pre-SAEOC cohort (Table 1). Although these differences did not reach statistical significance, the findings may suggest a potential benefit of structured multidisciplinary oversight, acknowledging the limitations of small sample size and treatment-era differences.A total of 21 providers completed surveys (Figure 1), with ≥80% reporting perceived improvements in timeliness of interventions, consistency and comprehensiveness of management, interdisciplinary communication, and confidence in SAE management (Figure 2). Respondents valued SAEOC contributions to management of complex cases such as IEC-parkinsonism, MAS/HLH, CNS infection, and multiorgan involvement. SAEOC implementation also contributed to refinement of institutional standard operating practices. Reported challenges included workload and meeting frequency. One respondent provided uniformly negative Likert ratings but described the intervention as highly beneficial in free text; this discordant response was kept but interpreted cautiously. Suggested improvements included streamlining activation, reducing meeting frequency when appropriate, formal recognition of provider effort, and greater incorporation of evidence-based frameworks.The SAEOC represents a model for early multidisciplinary engagement and provides a practical framework for harmonizing CAR-T toxicity management, particularly for complex cases.

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.

Immune checkpoint inhibitors (ICIs) are highly effective cancer therapies. However, they are associated with considerable adverse cardiovascular (CV) outcomes. We investigated the risk factors for CV hospitalisations and all-cause mortality in oncology patients receiving ICIs. A retrospective cohort study of adult patients administered ICIs between 1st January 2010 and 1st January 2020 in New South Wales, Australia. Electronic medical records were accessed to obtain demographic and clinical data. Univariate analysis included Chi-squared test for categorical variables and Student’s t-test for continuous variables. Binary logistic regression was used for multivariate analysis. Mortality was analysed using Cox regression including (i) time-dependent Cox models with CV admission as a time-varying covariate and (ii) a 1-year landmark sensitivity analysis. Out of 1,080 patients receiving ICIs during the study period, 340 patients (31.5

Significance: Immune checkpoint inhibitors (ICIs) have transformed cancer therapy by reactivating antitumor immunity and improving outcomes across multiple malignancies. Yet, clinical observations and preclinical studies suggest that ICIs may increase long-term cardiovascular disease risk, including hypertension, atherosclerosis, and thrombosis. The underlying mechanisms remain incompletely defined, highlighting the need for focused investigation into the vascular consequences of immune activation.Recent Advances: ICI-induced immune activation disrupts vascular and immune homeostasis through persistent production of reactive oxygen species (ROS), mitochondrial dysfunction, and accumulation of cell-free DNA (cfDNA). Sustained T-cell activation enhances ROS generation, driving DNA damage and senescence in both endothelial and immune cells. ICIs may also promote endothelial-to-mesenchymal transition (EndoMT) through chronic oxidative and inflammatory signaling, contributing to fibrosis, vascular stiffness, and chronic inflammation. Transforming growth factor-beta, although immunosuppressive in many contexts, can drive profibrotic and EndoMT programs within the vasculature. Other cytokines and regulators, including interleukin-17 and regulator of calcineurin 1, have been implicated in vascular remodeling, atherosclerosis, and hypertension.Critical Issues: The relative roles of ROS, mitochondrial dysfunction, cfDNA-driven inflammation, and EndoMT in ICI-associated vascular senescence remain unclear. While inflammation-induced vascular damage is well-recognized, direct ICI-specific mechanisms require stronger evidence. How senescent endothelial and immune cells influence therapy resistance and remodeling of the tumor microenvironment also remains to be defined.Future Directions: Mitochondrial and cytosolic ROS sources-arising from electron leakage during oxidative phosphorylation and NADPH oxidases activity-shape immune signaling and sustain T-cell activation during checkpoint blockade. The DNA damage response kinases ataxia-telangiectasia mutated and ATM- and Rad3-related, activated by oxidative and replicative stress, engage p53-dependent senescence pathways in endothelial and immune cells. Future studies should evaluate biomarkers such as cfDNA and thrombospondin-1 and explore senescence-targeting or redox-modulating interventions that may alleviate cardiovascular toxicity without diminishing antitumor efficacy. This review outlines mechanistic pathways linking ICIs to vascular dysfunction and senescence, integrating preclinical data with emerging clinical insights. It distinguishes established processes from ICI-specific hypotheses and identifies key gaps requiring clinical validation. Antioxid. Redox Signal. 00, 000-000.

Abstract Background Ionizing radiation (IR) accelerates atherosclerosis through induction of cellular senescence, DNA damage, defective efferocytosis, and dysregulation of clonal hematopoiesis (CH) drivers. Although low-dose colchicine reduces ischemic cardiovascular events in coronary artery disease, the precise molecular mechanisms underlying its vasculoprotective effects remain incompletely defined, and whether it mitigates radiation-associated vascular injury is unknown. Methods Bone marrow–derived macrophages (BMDMs) were pretreated with low-dose colchicine and exposed to 2 Gy IR. Molecular effects were assessed by RNA-seq, immunoblotting, and molecular docking. In vivo effects were tested in a partial carotid ligation (PLCL) model using spatial proteomics. Human monocyte-derived macrophages (HMDMs) from thoracic malignancy patients were analyzed before and after radiation therapy (RT). Results Low-dose colchicine suppressed IR-induced macrophage senescence signaling while preserving NRF2 activity. In a cell-free assay, colchicine directly activated aldehyde dehydrogenase 2 (ALDH2) in a dose-dependent manner (EC 50 1–5 nM), identifying ALDH2 as a direct molecular target of colchicine. Following irradiation, colchicine restored ALDH2, reduced mitochondrial (mt)ROS - dependent p90 ribosomal S6 kinase ( p90RSK ) activation and lipid peroxidation, preserved TET2 and DNMT3A expression, and rescued impaired efferocytosis while preventing nicotinamide adenine dinucleotide (NAD⁺) and adenosine triphosphate (ATP) depletion. These protective effects were ALDH2-dependent, as they were lost with ALDH2 inhibition or depletion and were mimicked by pharmacologic ALDH2 activation. In vivo, colchicine attenuated radiation-induced atherosclerosis and macrophage senescence-associated stemness (SAS). Consistently, macrophages from patients after RT showed reduced ALDH2 with increased mtROS, lipid peroxidation, and senescence. Conclusion These findings identify ALDH2 as a previously unrecognized molecular target of colchicine that links mitochondrial redox control to suppression of radiation-induced macrophage senescence and atherosclerosis and may contribute to the efficacy of low-dose colchicine in cardiovascular disease.

Aims Acute myocardial infarction (AMI) patients face a substantial risk of cardiovascular events and rehospitalization. The impact of the SmartHeart 12-lead electrocardiogram (ECG) telemedicine device on healthcare utilization has not been tested in a US randomized trial.Methods and results Patients with AMI were randomized at discharge to standard of care without (control group) or with the SmartHeart 12-lead ECG device (intervention group). The primary endpoint was the rate of emergency department (ED) visits, hospital readmissions, and any cardiovascular testing from discharge to 90 days of follow-up. The primary endpoint was reached in 57 (59%) patients in the control group and 53 (63%) patients in the intervention group (P = 0.61). However, in the intervention group, only 30% of patients complied with two follow-up training SmartHeart 12-lead ECG transmissions after discharge, and only 24% used the device thereafter. Among device users, ED presentations were lower in the intervention group than in the control group (8.0% vs. 29%, P = 0.04). In all patients advised to present to the ED upon device use (38%), a clinically relevant cardiovascular diagnosis was made. One patient survived a ventricular fibrillation cardiac arrest as advised to present to ED urgently after device use.Conclusion In this US-based RCT, there were no significant differences in the primary outcome in the intention-to-treat analysis. However, according to per-protocol analysis, proper use of the SmartHeart ECG device with 24/7 telemedicine support reduced inappropriate and increased appropriate ED presentations after hospitalization for AMI.

BACKGROUND:Atherothrombosis, which underlies most acute coronary syndromes and is driven by intraplaque thrombosis, preferentially occurs in regions of disturbed blood flow (d-flow). Although LATS1/2 (large tumor suppressor kinases 1 and 2) are known regulators of endothelial mechanotransduction, the mechanisms by which d-flow connects endothelial senescence, proliferation, and intraplaque thrombosis remain poorly understood. METHODS:We investigated endothelial cell (EC)-specific roles of Lats1/2 using inducible EC-specific knockout mice in a partial carotid ligation model. Spatial multiomics of human and mouse plaques was performed using imaging mass cytometry, COMET sequential immunofluorescence, and spatial metabolomics. RESULTS:Tamoxifen-induced deletion of both Lats1 and Lats2 (homozygous) in ECs caused fatal edema and increased vascular permeability. In contrast, Lats1het(±)/Lats2 homo(-/-)-EC-specific knockout mice survived and developed spontaneous atherothrombotic plaques with neovascularization. Spatial proteomics revealed that LATS1/2 loss induced a senescence-associated stemness phenotype driven by CD38 upregulation. Spatial metabolomics showed sulfite and taurine accumulation, indicating SUOX (sulfite oxidase) deficiency. CD38 suppressed SUOX, demonstrated a switch into the reverse mode of mitochondrial complex V, increased succinate dehydrogenase activity, and promoted ATP consumption. Despite ATP depletion, glutamate metabolism and the citric acid cycle flux increased, sustaining EC proliferation under energetic stress. This senescence-associated stemness state promoted both proliferation and senescence, leading to fragile, leaky neovessels and intraplaque thrombotic lesions. Pharmacological CD38 inhibition attenuated these phenotypes. Similar EC states were observed in human plaques. CONCLUSIONS:Loss of Lats1/2 in ECs induces a CD38-associated senescence-associated stemness-like phenotype that promotes intraplaque thrombosis through mitochondrial metabolic reprogramming, including changes consistent with reverse-mode operation of mitochondrial complex V. These findings define a mechanistic link between disturbed flow, endothelial metabolic reprogramming, and intraplaque thrombosis and hemorrhage.

Background/Objectives: While doxorubicin (DOX) and trastuzumab (TRZ) improve overall survival in women with breast cancer, these two anti-cancer drugs increase the risk of developing heart failure. As a novel and largely unexplored approach, our aim was to evaluate whether the prophylactic use of the sodium-glucose co-transporter 2 inhibitor empagliflozin (EMPA), with and without the angiotensin converting enzyme inhibitor perindopril (PER), is cardioprotective in preventing DOX + TRZ-mediated cardiotoxicity. Methods: In a chronic in vivo murine model, female mice received prophylactic treatment with PER (3 mg/kg), EMPA (10 mg/kg), or EMPA + PER via oral gavage for a total of 3 weeks as a run-in period prior to weekly administration of DOX + TRZ (8 mg/kg and 3 mg/kg, respectively) intraperitoneally for an additional 3 weeks (total of 6 weeks). Results: In mice treated with DOX + TRZ, the left ventricular ejection fraction (LVEF) decreased from 75 ± 2% at baseline to 40 ± 4% at week 6. Prophylactic treatment with either PER, EMPA, or EMPA+PER improved LVEF to 58 ± 3%, 66 ± 3%, and 67 ± 4% at week 6, respectively (p < 0.05). Histological analyses confirmed significant disruption of myofibrils, vacuolization, and loss of sarcomere integrity in the DOX + TRZ-treated mice. Prophylactic administration with PER, EMPA, or EMPA + PER, however, improved myofibril integrity at week 6 in mice receiving DOX + TRZ. Finally, although the Bax/Bcl-xL ratio was significantly elevated by 1.5-fold in mice treated with DOX + TRZ, this marker of apoptosis was attenuated by prophylactic treatment with either PER, EMPA, or EMPA + PER. Conclusions: Prophylactic administration of EMPA mitigated adverse cardiovascular remodeling in a chronic in vivo model of DOX + TRZ-mediated cardiotoxicity.

BACKGROUND:Immune checkpoint inhibitors (ICIs) have transformed cancer treatment, yet their use carries the risk of ICI-related myocarditis (ICIrM), a rare but potentially fatal adverse event. Although the overall incidence of ICIrM has been described, recent trends and diagnostic shifts remain poorly characterized. METHODS:We retrospectively reviewed 11,602 patients treated with ICIs at a multi-center institution from 2011 to 2024. ICIrM cases were identified through manual chart review, and baseline characteristics, cardiovascular events, and outcomes were assessed. The study was designed as a descriptive analysis of temporal trends in ICI therapy use and ICIrM. RESULTS:ICIrM occurred in 127 patients (1.1%), with a mean age of 66.7 ± 12.7 years and 56.5% male. Median time to onset was 45 days (IQR 106). ICI use increased steadily over the past decade, with a marked rise in ICIrM diagnoses in 2023-2024, accounting for 47.2% of all cases. Diagnostic prevalence rose from 0.5% before 2020 to 1.3% after 2020, likely reflecting enhanced recognition due to the implementation of guideline-based diagnostic criteria (Bonaca et al. and ESC-ICOS). Seasonal variation in ICIrM incidence was not observed. CONCLUSIONS:The increasing incidence of ICIrM likely reflects improved clinical awareness and diagnostic practices. Continued efforts to optimize surveillance, early detection, and mitigation strategies are essential as ICI use expands globally.

ABSTRACT Introduction and Methods Cancer therapy–related cardiac dysfunction (CTRCD) is a well established and potentially life‐threatening complication of contemporary oncologic treatment. Although comprehensive cardio‐oncology guidelines have been developed, their integration into routine hematology and oncology practice remains inconsistent. This consensus statement, developed by a multidisciplinary panel of cardio‐oncology experts, aims to provide practical, case‐based guidance to help oncology providers recognize, assess, and manage CTRCD across a spectrum of malignancies and cardiovascular presentations. Clinical Scenarios and Discussion We present representative clinical scenarios that illustrate real‐world challenges in cardio‐oncology and apply evidence‐based recommendations from current guidelines, including those from the European Society of Cardiology (ESC) and the International Cardio‐Oncology Society (ICOS)—to support informed decision‐making. Key areas of focus include baseline cardiovascular risk stratification prior to initiating potentially cardiotoxic therapies, with an emphasis on biomarker and imaging surveillance strategies tailored to individual risk profiles. Also, this document outlines the application of guideline‐directed medical therapy (GDMT) for cancer patients with heart failure. Conclusion By offering a structured, user‐friendly framework, this document seeks to bridge the implementation gap between oncology and cardiology disciplines. Our goal is to equip oncology providers with accessible tools that facilitate early recognition, consistent surveillance, and timely referral, thereby preserving cancer treatment intensity while minimizing cardiovascular morbidity.

Aims:Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) reduce major adverse cardiovascular events in diabetics. This study aimed to investigate the cardiac, cancer, and overall mortality effects of GLP-1 RAs in diabetics treated with anthracyclines. Methods and results:We retrospectively identified 1384 diabetics treated with anthracyclines from 2013 to 2023; 56 received GLP-1 RAs between their first and last dose of anthracycline. These patients were propensity score matched 4:1 to 224 controls without concurrent GLP-1 RA use. Because stage was not available for 10 of the 56 patients, a repeat analysis was conducted with additional matching for cancer stage in 46 cases and 92 controls. Major endpoints were rate of all-cause and cancer-related and cardiovascular disease (CVD)-related mortality, no evidence of disease (NED), and hospitalization for CVD including heart failure (HF), over 5 years. Survival analyses were conducted using cause-specific hazards Cox regression. Patients on GLP-1 RAs had a significantly lower 5 year overall mortality (HR 0.46, CI 0.24-0.87, P = 0.007) and cancer-related mortality (HR 0.42, CI 0.19-0.91, P = 0.03). This mortality risk reduction remained significant even when accounting for covariates (HR 0.39, CI 0.20-0.75, P = 0.002). The percentage of patients with NED was higher in the GLP-1 RA than control group (60.9% vs. 38.0%, P = 0.007). A decline in left ventricular ejection fraction was seen in controls but not in patients on GLP-1 RAs. There was no significant difference in CVD hospitalization; the rate of HF-related hospitalization was very low overall. Conclusion:GLP-1 RAs may offer survival benefits and better cancer- and cardiac function-related outcomes in diabetics undergoing anthracycline chemotherapy.