The Bruton’s tyrosine kinase (BTK) inhibitor ibrutinib has revolutionized treatment for B-cell malignancies but increases the incidence of atrial fibrillation (AF) compared to conventional chemotherapy. The downstream signaling pathways through which ibrutinib leads to AF are unknown and may represent a novel molecular mechanism for AF. To identify kinase signaling pathways that promote atrial fibrillation during ibrutinib therapy. Studies were performed in human atrial-specific cardiomyocytes derived from population control induced pluripotent stem cells (hiPSC-aCMs). Electrophysiologic measurements, including extracellular field potentials (EFPs), were conducted with the Nanion CardioExcyte96 system. Human phospho-kinase arrays determined the relative phosphorylation of 37 kinases in hiPSC-aCMs treated with either ibrutinib or vehicle control. Extracellular field potentials demonstrated a marked increase in spontaneous beat-to-beat variability, an in vitro correlate of arrhythmogenic behavior, with exposure to ibrutinib but not to second or third-generation BTK inhibitors, which are less associated with AF. Treatment with ibrutinib increased phosphorylation of multiple kinases (Src, Erk1/2, CREB) in the Src-Erk1/2 pathway; the most significant increase was with Erk1/2 phosphorylation (threefold). Pre-treatment of hiPSC-aCMs with the Erk1/2 inhibitors ulixertinib and SCH772984 inhibited the EFP arrhythmogenic signal seen with ibrutinib. In hiPSC-aCMs, ibrutinib treatment leads to increased arrhythmogenic behavior via the Src-Erk1/2 phosphorylation pathway. The inhibition of Erk1/2 or its downstream targets may represent novel pathways in the development of atrial fibrillation, providing new targets for therapeutic development.
In recent years, the field of Cardio-Oncology has expanded beyond its traditional focus on cancer therapy–related cardiotoxicity. Growing evidence now supports a bidirectional relationship between cardiovascular disease (CVD) and cancer, in which CVD may promote tumor progression. Multiple epidemiological studies across diverse CVD phenotypes—including atherosclerosis, hypertension, myocardial infarction, atrial fibrillation and heart failure (HF)—point towards higher cancer incidence and mortality, extending beyond shared risk factors and pathophysiological pathways. Furthermore, animal experimentation has provided mechanistic clues linking cardiac injury to exacerbated cancer progression. Proposed mechanisms include cardiac secretion of tumor‑potentiating proteins and small extracellular vesicles, immune reprogramming and HF-associated gut microbiome dysbiosis. Notably, the impact of CVD on tumor progression appears cancer‑type-specific and may vary across tumor models, underscoring biological heterogeneity in heart-to-tumor crosstalk. In this review, we provide an overview of epidemiological and mechanistic evidence linking CVD to increased tumor growth. Additionally, we performed an analysis of literature-reported chronic HF biomarkers and their association with cancer. This analysis identified a subset of HF biomarkers with strong associations across multiple cancer types, highlighting potential molecular mediators of CVD-induced oncogenic signaling. Collectively, current evidence from epidemiological, experimental and computational data indicates a complex biological and potentially causal relationship between CVD and cancer, involving multiple mechanisms. Advancing mechanistic understanding may improve oncological risk stratification in CVD populations, guide the development of targeted strategies to disrupt heart-to-tumor signaling and strengthen the foundation for integrated Cardio-Oncology care.
Patients with severe coronary artery disease (CAD) requiring time-sensitive gastrointestinal cancer surgery face a dual challenge: perioperative myocardial ischemia and surgical bleeding. The optimal management strategy in this setting remains undefined. This single-center retrospective cohort study evaluated the association between prophylactic intra-aortic balloon pump (IABP) placement and perioperative outcomes in 100 patients with angiographically confirmed severe CAD who underwent gastrointestinal cancer surgery between February 2014 and May 2024. Fifty patients received preoperative prophylactic IABP, and 50 served as controls. The primary combined endpoint was perioperative major adverse cardiovascular events (MACE) and all-cause mortality. Secondary outcomes included major bleeding and intensive care unit admission. As a post-hoc sensitivity analysis, propensity score matching (1:1 nearest neighbor, caliper 0.02) was performed based on the number of diseased vessels to further explore the robustness of the findings. Prophylactic IABP significantly outperformed conventional management in terms of reducing the primary combined endpoint (4.0
Childhood cancer survivors (CCS) are at elevated risk for cardiovascular disease due to cardiotoxic cancer therapies. Different international guidelines and recommendations for follow-up were published. However, global practices surrounding cardiovascular risk assessment, screening, and management in CCS remain variable and incompletely characterized. A 20-question survey was created by the Pediatric Working Group of the International Cardio-Oncology Society (ICOS) for medical practitioners involved in the care of CCS to assess current practices in cardiovascular risk evaluation, preventive strategies, screening modalities, cardiology referral, and heart failure (HF) management. The survey distribution was a collaborative effort by ICOS pediatric work group leaders. Descriptive statistics were used to summarize responses. A total of 123 unique practitioners responded, with 75
Routine inflammatory and cardiac biomarkers may help risk-stratify patients receiving immune checkpoint inhibitors (ICIs). The ECG monitoring endpoint and oncologic survival outcomes are distinct. We examined whether baseline cardiac biomarkers were associated with adjudicated new-onset electrocardiographic (ECG) abnormalities after ICI initiation and whether inflammatory and cardiac biomarkers were associated with overall survival (OS) and progression-free survival (PFS). This single-center retrospective cohort included 162 patients with advanced gastrointestinal or lung cancers who received at least two cycles of ICI monotherapy or ICI-based combination therapy. The ECG monitoring endpoint was any adjudicated new-onset ECG abnormality. Baseline ECGs were used to identify pre-existing findings, and ICI initiation was the time origin for the 12-month Cox, Kaplan–Meier, and score analyses. Patients without an event were censored at the earliest of the last evaluable ECG date, death, or 365 days after ICI initiation. ECGs were independently reviewed by two cardiologists, and disagreements were resolved by consensus. Logistic regression and Cox models were used for ECG, OS, and PFS analyses; age-stratified Cox sensitivity analyses addressed non-proportionality. New-onset ECG abnormalities occurred in 86 patients (53.1
Aromatase inhibitors (AIs) and tamoxifen (TAM) are standard adjuvant endocrine therapies for postmenopausal women with hormone receptor–positive breast cancer. Although prior studies suggest a higher overall cardiovascular risk with AIs, the specific cardiovascular phenotypes driving this risk in real-world breast cancer survivors remain incompletely characterized. We conducted a retrospective cohort study using the TriNetX Global Collaborative Network. Women aged ≥ 50 years with stage I–III breast cancer who newly initiated AIs or TAM between 2010 and 2024 were included. A 1:1 propensity score–matched new-user design with a 6-month lag period was applied. Cardiovascular outcomes were grouped a priori into three phenotype-specific composites: atherosclerotic/vascular disease, myocardial dysfunction/electrical instability, and thromboembolic disease. Inflammatory cardiac disorders were evaluated separately as exploratory outcomes. Hazard ratios (HRs) were estimated using Cox proportional hazards models. After matching, each treatment group included 33,974 patients. During up to 5 years of follow-up, AI users had a higher cumulative incidence of composite CVD outcome than TAM users (19.81
Radiation-induced heart disease (RIHD) is a serious complication following radiotherapy for thoracic malignancies. Early diagnosis is challenging due to the lack of specific biomarkers. This study aimed to screen potential plasma biomarkers for RIHD using metabolomics and construct high-accuracy diagnostic models. A total of 57 RIHD patients and 22 healthy controls (HC) were enrolled. Untargeted metabolomic profiling of plasma samples was performed using gas chromatography–mass spectrometry (GC–MS). Differential metabolites were screened by combining multivariate statistical analysis and univariate analysis. Metabolic pathway enrichment analysis was conducted. Three machine learning models—Support Vector Machine (SVM), Linear Discriminant Analysis (LDA), and Random Forest (RF)—were constructed based on the identified biomarkers, and their diagnostic performance was evaluated. A total of 44 differential metabolites (6 upregulated, 38 downregulated) were identified between the RIHD and HC groups. These metabolites were primarily involved in phenylalanine/tyrosine/tryptophan biosynthesis, arginine biosynthesis, the TCA cycle, and glycine/serine/threonine metabolism. Variable importance analysis based on random forest algorithms identified key metabolites such as lysine and cysteine as significant contributors to group separation. The Random Forest diagnostic model demonstrated the best performance in the test set, achieving an area under the curve (AUC) of 0.872 (95
Cardiovascular disease remains the leading cause of morbidity and mortality among cancer survivors. Multiple cardiovascular risk prediction models exist to provide risk stratification for patients who are about to undergo cancer treatment. Current risk models have limited guidance on how to prevent, modify, and monitor for heart failure (HF) particularly heart failure with preserved ejection fraction (HFpEF). Cancer survivors are at an elevated risk for HFpEF due to the development of cardiometabolic syndrome associated with aging and long-term survival. Future efforts should focus on novel biomarkers in assessing HF, development of large, multicenter databases that can be used to validate models across diverse populations, and defining clear treatment pathways once risk is identified. A more comprehensive and inclusive risk stratification model with pragmatic approaches to clinical care will allow for more widespread use among cardiologists and oncologists.
Cardiovascular and pro-atherogenic side-effects of chemoradiotherapy for non-small cell lung cancer (NSCLC) remain a major concern given the growing burden of cancer therapy-related cardiovascular disease. Atherosclerotic plaque burden can be measured using calcium scoring while plaque activity can be assessed using [18F]fluorodeoxyglucose ([18F]FDG) positron emission tomography (PET). To investigate the impact of chemoradiotherapy on aortic atherosclerotic burden and disease activity in patients with advanced NSCLC undergoing repeated [18F]FDG PET and computed tomography (CT) scans. All [18F]FDG PET-CT scans of patients with stage 3B NSCLC from the American College of Radiology Imaging Network (ACRIN 6668) trial were retrieved from the Cancer Imaging Archive. Volumes of interest for the aorta, left ventricle and major non-cardiac organs were manually delineated. Calcium scores, mean standard uptake values (SUVmean) and target-to-background ratios (TBRmean) were quantified, and comparisons before and after treatment scans performed. Twenty-six patients (mean 60 ± 9 years, body-mass index 25 ± 5 kg/m2) met the inclusion criteria, with 23 having aortic atherosclerosis as evidenced by the presence of aortic calcification. Pre- and post-treatment scans were performed approximately 14 weeks apart. After chemoradiotherapy, aortic calcium score increased by 10
As cancer survival rates improve, focus has moved toward managing long-term treatment-related toxicities such as cardiovascular disease (CVD). Radiation is an important modality of treatment for many cancers; however, its use can lead to cardiovascular disease by accelerating the formation of coronary artery atherosclerosis. Coronary artery calcium (CAC) scoring from computed tomography (CT) scans offer a non-invasive method to assess CVD risk. Cancer patients undergoing thoracic radiotherapy require a CT scan of the chest for planning purposes. The primary aim of this study was to assess the feasibility of using radiotherapy planning CT scans to calculate CAC scores in cancer patients and establish a cardio-oncology referral pathway. Secondary aims were to evaluate the impact of CAC scoring on anxiety and quality of life (QoL); and assess adherence to cardio-oncology referral pathway. A multicentre, prospective observational study recruited 101 eligible cancer survivors (predominantly women with breast cancer) undergoing thoracic radiotherapy. CAC scores were calculated from planning CT scans, and participants with CAC > 0 were referred to cardio-oncology. QoL and anxiety were measured at baseline, shortly after CAC disclosure, and three months post-radiotherapy. Adherence to cardio-oncology referrals was recorded. CAC scores were successfully calculated for all participants; 31
Cardiac toxicity remains a relevant concern in breast cancer radiotherapy. Both incidental dose to specific cardiac substructures and pre-existing coronary calcifications may impact long-term outcomes. This study evaluated the prognostic significance of these two complementary predictors in a Chilean cohort of breast cancer patients undergoing thoracic radiotherapy. This retrospective cohort study included 375 breast cancer patients treated at UC-Christus Health Network (1985–2022), comprising 61 deceased and 314 non-deceased patients. Cardiac substructures were automatically segmented using an open-source algorithm. Cardiac calcium burden was quantified from non-contrast planning computed tomography (CT) using a 130 HU threshold. Dose distributions were converted to equivalent dose in 2 Gy fractions. Univariate Cox regression with false discovery rate correction and graph-based collinearity selection were applied, followed by multivariable Cox models adjusted for relevant clinical covariates and cardiac calcium burden. Cardiac calcium burden was independently associated with OS after adjustment for clinical covariates. Among dosimetric parameters, three metrics survived collinearity elimination and remained independently associated with overall survival (OS) in separate multivariable models: composite cardiac base region (C1) mean dose, right ventricle (RV) mean dose, and RV-V10Gy. Kaplan–Meier analyses confirmed progressive survival differences across calcium burden catefum burden and radiation dose to the C1 region and RV were independently associated with OS in breast cancer patients receiving thoracic radiotherapy. Cardiac calcium quantification from routine planning CT represents a clinically actionable tool for cardiovascular risk stratification within the existing radiotherapy workflow. This study also provides the first Latin American validation of an open-source automated cardiac segmentation tool in a breast cancer radiotherapy cohort. gories and RV-based dosimetric risk groups, while no statistically significant separation was observed for C1 mean dose groups, when restricting the minimum group size. Automated segmentation demonstrated high accuracy for whole-heart delineation, while geometric accuracy for left anterior descending artery segmentation was limited. Pre-treatment cardiac calcium burden and radiation dose to the C1 region and RV were independently associated with OS in breast cancer patients receiving thoracic radiotherapy. Cardiac calcium quantification from routine planning CT represents a clinically actionable tool for cardiovascular risk stratification within the existing radiotherapy workflow. This study also provides the first Latin American validation of an open-source automated cardiac segmentation tool in a breast cancer radiotherapy cohort.
As increased muscle mass and decreased fat mass are associated with improved survival after breast cancer treatment, herein we compare two regimens for conditioning and skeletal muscle hypertrophy (SMH) to assess their impact on body composition and VO2 max. Fifteen participants were prospectively assessed during four exercise regimens for changes in body composition and VO2 max before and after each regimen. Participants underwent four weeks of conditioning, followed by four weeks of SMH training. After a four-week washout period, they underwent conditioning followed by SMH. In total, 15 participants completed the 20-week regimen. Prior to enrollment, all participants had previously completed at least 3 months of supervised, dose-escalated resistance training, with ongoing pre-regimen resistance training for median duration of 11.32 months (IQR). Median age at enrollment was 51 years, with 73
Chronic lymphocytic leukemia (CLL) is the most prevalent leukemia in adults in the Western countries. Ibrutinib, a first-generation Bruton’s tyrosine kinase (BTK) inhibitor, is commonly used for relapsed/refractory CLL but is associated with cardiovascular adverse effects such as atrial fibrillation (AF) and hypertension (HTN). Zanubrutinib, a second-generation BTK inhibitor, was developed with greater BTK selectivity to reduce off-target toxicity. However, comparative data on zanubrutinib versus chemoimmunotherapy in CLL remain limited. This retrospective cohort study used the TriNetX platform to compare patients treated with zanubrutinib versus those receiving chemoimmunotherapy. Propensity score matching was performed to balance demographic and clinical characteristics. Primary outcomes included all-cause mortality and cardiovascular events: AF/atrial flutter, HTN, acute heart failure, ventricular arrhythmias, and bleeding. There was no ethical or IRB approval required for this study. Proportional-hazards assumptions were assessed using Schoenfeld residuals, and pre-specified sensitivity and severity-surrogate analyses were performed. After matching (1,231 per cohort), all-cause mortality was similar between zanubrutinib and chemoimmunotherapy (HR 0.99; p = 0.95). Zanubrutinib showed significantly fewer cardiotoxic events (HR 0.77; p = 0.001) and lower incident atrial fibrillation/flutter (HR 0.65; p = 0.04). Rates of hypertension, heart failure, ventricular arrhythmias, and bleeding were comparable (all p > 0.20). Predictors of bleeding included anticoagulant use, chronic kidney disease, and liver disease. The proportional-hazards assumption was not violated for atrial fibrillation/flutter (Schoenfeld p = 0.92), and sensitivity analyses showed directionally consistent results. Procedural and pharmacologic severity surrogates were also comparable between groups. In this propensity-matched real-world analysis, zanubrutinib was associated with similar 2-year mortality and lower observed cardiotoxicity, particularly incident atrial fibrillation/flutter, compared with B-CIT. These findings suggest a potentially favorable cardiovascular safety profile for zanubrutinib, although residual confounding, treatment-selection bias, and limitations of EHR-based outcome capture preclude causal inference. Prospective comparative studies are warranted.
Cancer therapy related cardiac dysfunction (CTRCD) is a major concern in breast cancer patients, often reducing left ventricular ejection fraction (LVEF) and causing symptomatic heart failure. This study assessed the comparative effectiveness and safety of cardioprotective drugs in preserving LVEF during chemotherapy. Our database search, included Cochrane, PubMed, WOS, and SCOPUS, from inception to May 1st, 2024, to find randomized controlled trials (RCTs) that assessed the effectiveness and safety of cardioprotective drugs in breast cancer patients undergoing chemotherapy. Bayesian network meta-analysis and meta-regression were performed using the BUGSnet package in R studio version 4.4.2, applying a random-effects model, and mean differences (MD) with 95
Cancer therapy–related cardiac dysfunction (CTRCD) is a frequent and clinically relevant complication in patients with lymphoma treated with anthracyclines. Early identification of subclinical myocardial injury is critical to prevent progression to overt heart failure and to avoid chemotherapy dose reductions that may compromise oncologic outcomes. We aimed to evaluate the role of cardiac magnetic resonance (CMR) with T1 mapping and feature-tracking myocardial strain, in comparison with transthoracic echocardiography (TTE) and circulating biomarkers, for the early detection of CTRCD in lymphoma patients receiving anthracycline-based chemotherapy. In this prospective, single-center observational study, forty-nine adult patients with lymphoma scheduled for anthracycline-based chemotherapy underwent serial assessment of high-sensitivity cardiac troponin T (hs-cTnT), NT-proBNP, TTE, and CMR at baseline (visit 0), after the third chemotherapy cycle (visit 1), and at chemotherapy completion (visit 2). TTE was repeated at 12-month follow-up (visit 3). CMR included cine imaging, T1 mapping with extracellular volume (ECV) quantification, late gadolinium enhancement, and feature-tracking strain analysis (global longitudinal [GLS], circumferential [GCS], and radial [GRS] strain). CTRCD was defined and graded according to the 2022 ESC Cardio-Oncology Guidelines. The median age of patients was 46 (29.5–62) years; 53.1
The quest for new, reliable prognostic markers of cardiovascular toxicity in patients undergoing anthracycline therapy remains a crucial challenge. The serum hemoglobin-to-creatinine ratio (Hb/Cr) has never been investigated in this setting. We explored the association between the Hb/Cr ratio and early surrogate markers of anthracycline-related cardiotoxicity in patients with hematological disorders. Among 171 patients included in a retrospective registry, 7 were excluded due to missing data. Patients underwent echocardiographic evaluation before and after at least one cycle of anthracycline-based chemotherapy, over a median follow-up of 135 days. The primary endpoint was post-chemotherapy cardiac dysfunction (PCCD), defined as a composite of reduced left ventricular ejection fraction, new-onset diastolic dysfunction, or increased left ventricular end-diastolic diameter. Patients were stratified into low versus high Hb/Cr groups. After at least one chemotherapy cycle, PCCD occurred more frequently in patients with lower Hb/Cr values (57.5
The Eastern Cooperative Oncology Group Performance Status (ECOG-PS) is central to cancer care planning and prognostication. Whether ECOG-PS also carries prognostic value in the setting of primary thromboprophylaxis for cancer-associated venous thromboembolism (VTE) remains unknown. To evaluate the impact of ECOG-PS on clinical outcomes in ambulatory patients with cancer initiating chemotherapy. This was a post-hoc analysis of the AVERT randomized controlled trial that evaluated apixaban (2.5 mg twice daily) for thromboprophylaxis in patients at intermediate-to-high VTE risk. Multivariable survival models assessed the association between ECOG-PS (0–1 versus 2–3) and the composite primary outcome of VTE or clinically relevant bleeding (CRB), as well as its individual components and all-cause mortality, over 180 days. Of 428 patients included, 368 (86.0
Cancer and atrial fibrillation frequently coexist. Intensive care adds hemodynamic stress, organ failure, and competing bleeding risk. Whether platelet-defined thrombocytopenia modifies the association between an ICU-onset atrial fibrillation surrogate and short-term outcomes in patients with cancer remains uncertain. We performed a secondary analysis of a retrospective ICU cohort derived from MIMIC-IV version 3.1, a de-identified critical care database with date-shifted patient timelines. Adult ICU stays with solid or hematologic malignancy were included. The exposure was an ICU-onset AF surrogate rather than adjudicated incident AF. Early thrombocytopenia was defined from the minimum platelet count within 48 h and categorized as > = 150, 100–149, 50–99, and < 50 × 10^9/L. The primary outcome was in-hospital death. Secondary outcomes were 28-day death, major bleeding identified by ICD coding, and ischemic stroke identified by ICD coding. Multivariable logistic regression tested AF-by-platelet interaction. Sensitivity models added available cancer-site, cardiovascular comorbidity, major surgery, structured anticancer medication indicators, and anticoagulation dose-class variables. Among 9,640 cancer ICU stays, 1,788 (18.5
Cardiovascular disease (CVD) is a major concern among cancer survivors. However, the intersection of cancer and CVD has only recently gained broader attention, and substantial evidence gaps remain. This study aimed to identify risk factors associated with incident CVD in cancer survivors and to develop a machine learning model for CVD risk prediction. In this retrospective study, we included 2,500 patients receiving systemic antitumor therapy at Jilin Cancer Hospital; 188 incident CVD events were observed. Variables spanning demographic, clinical, tumor- and treatment-related, and laboratory domains were collected. The dataset was randomly split into a training set (75
Myocardial infarction and ischemic stroke are common causes of morbidity after major cancer surgery. Understanding the risks associated with both open and laparoscopic surgery is crucial in reducing postoperative morbidity and mortality. This nationwide cohort study included patients who underwent major cancer surgery in the pelvis from 2000 to 2015. The primary outcome was the incidence of myocardial infarction and ischemic stroke within 90 days postoperatively. Adjusted odds ratios (OR) were estimated using logistic regression adjusted for propensity score and risks by regression standardization. A total of 22,619 patients operated with laparoscopic and 70,896 patients operated with open approach were included in the analysis. The crude 90-day cumulative risks of myocardial infarction and ischemic stroke were 0.66
