Cardiotoxic Therapy Research Articles

When to intervene in aortic stenosis; can cardiac troponin I in the first morning urine be our guide?

Aortic stenosis is one of the most prevalent acquired valvular diseases in the Western world. Despite its high incidence, timely intervention through valve replacement remains a diagnostic challenge. Recent studies suggest that measuring cardiac troponins in the first morning urine may have potential clinical applications. In healthy individuals, concentrations of troponin I in the first morning urine are several times higher than in plasma. Various conditions that damage the heart, such as arterial emergencies or cardiotoxic therapy, lead to an increased concentration of cardiac troponin I in the first morning urine. Conversely, in patients with severe aortic stenosis scheduled for operative treatment, concentrations of cardiac troponin I in the first morning urine are barely detectable. This phenomenon may result from myocardial remodeling and altered clearance of troponin I from the heart. We hypothesize that reduction in the concentration of troponin I in the first morning urine indicates the onset of cardiomyocyte necrosis, adverse myocardial remodeling, and myocardial fibrosis during the progression of aortic stenosis.

Abstract 4135712: Mortality and Cardiovascular Complications Associated with Weight Loss Drugs among Breast Cancer Females Under Cardiotoxic Therapies: A Real-World Populational Study in the United States

Background: Obesity is an adverse prognostic factor for breast cancer (BC). While liraglutide and semaglutide, derived from antidiabetic glucagon-like peptide-1 receptor agonists (GLP1RA), are established weight loss drugs known for their cardiovascular safety in the general obese population, their safety in BC patients undergoing cardiotoxic antineoplastic therapies remains less understood. Objective: To investigate the mortality and cardiovascular outcomes related to GLP1RA used for weight loss among the highly susceptible BC females. Methods: This retrospective cohort study was based on the TrinetX network, comprising real-time health records from over 60 US healthcare organizations. The study population included obese females (≥18 years old) who received at least three prescriptions of either exclusive GLP1RA (liraglutide or semaglutide) or non-GLP1RA weight loss drugs (phentermine, bupropion-naltrexone, orlistat) upon BC diagnosis between 01/01/2015 and 01/01/2022. The index date was the initiation of systemic anti-cancer treatment, including chemotherapy (anthracycline, taxane, or cyclophosphamide), and/or anti-HER2 agents (trastuzumab, pertuzumab, or lapatinib). We used 1:1 propensity score-matching (PSM) to balance demographics, BMI, comorbidities, concurrent medications for cardiovascular diseases and metabolic disorders, BC receptor status and prior treatment, and levels of serum cholesterol (LDL, HDL) and hemoglobin A1c. Cox regression models were applied to compute hazard ratios (HR) and 95% confidence intervals (CIs). Follow-up continued until 05/24/2024, or until adverse cardiovascular events or death occurred. Results: Among 380 PSM-balanced pairs, the GLP1RA group (mean age: 57.6±11) showed significantly lower risks of all-cause mortality (HR 0.593, 95% CI 0.457-0.77), acute heart failure (HR 0.496, 95% CI 0.286-0.859), angina pectoris (HR 0.566, 95% CI 0.343-0.936), and acute stroke (HR 0.661, 95% CI 0.46-0.951) than the non-GLP1RA group (mean age: 57.5±12). Otherwise, no significant difference was shown in acute myocardial infarction (HR 0.787, 95% CI 0.495-1.251), pulmonary hypertension (HR 0.777, 95% CI 0.55-1.099), or arrhythmias (HR 0.829, 95% CI 0.566-1.215). Conclusion: Compared to non-GLP1RA weight loss agents, GLP1RA offers better survival and cardiovascular protection for BC patients undergoing cardiotoxic therapies. Future studies are warranted to validate the safety of these weight loss drugs during the BC treatment continuum.

Abstract 4144553: Fully Automated Machine Learning Based Echocardiographic Assessment of Global Longitudinal Strain in Breast Cancer Patients Receiving Cardiotoxic Chemotherapy

Background: Global longitudinal strain (GLS) is considered the most sensitive echocardiographic marker for detecting cardiotoxicity and subclinical changes in cardiac function in patients receiving cardiotoxic therapies. Despite literature that has shown less inter-observer variability for GLS compared to left ventricular ejection fraction, there remains significant variability in GLS measurement across observers and vendors. US2.AI is a novel, machine learning-based artificial intelligence (AI) algorithm for automated echocardiographic interpretation. We aim to demonstrate the feasibility of AI-based GLS assessment and hypothesize that AI-based GLS measurement is more reproducible compared to human-based measurement Methods: A total of 27 transthoracic echocardiograms were selected at random from a population of female cardio-oncology breast cancer patients and were run through the US2.AI algorithm twice to calculate GLS. The same echocardiograms were then analyzed by two board-certified cardiologists in a blinded fashion to calculate GLS using QLAB software (Philips). The two methods of GLS measurement (AI versus humans) were compared using linear regression, as assessed by the Pearson correlation coefficient. Reproducibility for each method was assessed using the intra-class correlation coefficient (ICC). Results: A total of 27 studies were analyzed with a mean age of 55.6 ± 11.3 and all patients were female. The feasibility of US2.AI for the assessment of GLS was demonstrated with a strong correlation between AI-based and human reads (r = 0.80, p < 0.00001). The reproducibility of AI-based GLS assessment was superior to that of human readers as assessed by an ICC of 1.0 versus 0.52, respectively. Conclusion: AI-based assessment of GLS was shown to be both feasible and more reproducible compared to expert human readers in a population of breast cancer patients receiving cardiotoxic chemotherapy. Given the important clinical implications of GLS in cardio-oncology patients, more widespread implementation of AI-based strain assessment has the potential to significantly improve the reproducibility of GLS measurement in this unique patient population.

Cardiac health in breast cancer (CHiB): protocol for a single-centre, randomised controlled trial.

The incidence of breast cancer has increased from 900 000 to 2.3 million new annual cases over the last 25 years. The 5-year survival rate has markedly risen to over 90% worldwide due to significant therapeutic advancements. Longer survival in patients with breast cancer means more patients may experience long-term effects of their treatments, including cancer therapy-related cardiac dysfunction (CTRCD). To date, there is no established primary prevention to minimise CTRCD. The Cardiac Health in Breast Cancer study is a two-arm, single-centre, randomised controlled trial investigating the impact of an exercise programme on cardiac changes in patients with breast cancer undergoing cardiotoxic cancer therapy. 48 females with breast cancer will be randomised to either a 12-month intervention group (IG) or a control group (CG). The IG will receive a combination of supervised high-intensity interval training (HIIT) and high-intensity resistance training (HIRT) for 6 months, while the CG will follow WHO guidelines for physical activity independently. All participants will undergo transthoracic echocardiography, cardiac magnetic resonance (CMR) imaging and cardiopulmonary exercise testing at baseline, after 6 months and after 12 months. The primary endpoint is the occurrence of symptomatic or asymptomatic CTRCD at the time points of examination, detected by cardiac imaging, which may be mitigated by structured physical exercise. Secondary endpoints include assessments of cardiac inflammation as detected by CMR, mitochondrial dysfunction, health-related quality of life, the occurrence of fatigue, depression and anxiety, as well as exercise capacity, average heart rate, heart rate variability and daily physical activity.

A Randomized Controlled Trial of Gamification to Increase Physical Activity Among Black and Hispanic Breast and Prostate Cancer Survivors: Rationale and Design of the ALLSTAR Clinical Trial

Survivors of breast and prostate cancer, especially those that are Black and/or Hispanic, are at high risk for cardiovascular events. Physical activity can reduce the risk of cardiovascular events in cancer survivors, but Black and Hispanic people are less likely to engage in routine physical activity. Concepts from behavioral economics have been used to design scalable, low-touch, gamification interventions that increase physical activity in individuals at high risk for cardiovascular events, but the effectiveness of these strategies in Black and Hispanic survivors of breast and prostate cancer is uncertain. ALLSTAR (NCT05176756) is a pragmatic, virtual, randomized controlled trial designed to evaluate the effectiveness of a gamification intervention informed by behavioral economic concepts to increase daily physical activity in Black and Hispanic breast and prostate cancer survivors who received cardiotoxic therapies and have additional risk factors for cardiovascular disease. Patients were either referred by their cancer care team or identified by electronic health record searches; contacted by letter, email, text message and/or phone; and complete enrollment and informed consent on the Penn Way to Health online platform. Patients are then provided with a wearable fitness tracker, establish a baseline daily step count, set a goal to increase daily step count by 1500-3000 steps from baseline, and are randomized 1:1 to control or gamification. Interventions continue for 6 months, with follow-up for an additional 3 months to evaluate the durability of behavior change. The trial has met its enrollment goal of 150 participants, with a primary endpoint of change from baseline in daily steps over the 6-month intervention period. Key secondary endpoints include change from baseline in daily steps over the 3-month post-intervention follow-up period, change in moderate to vigorous physical activity over the intervention and follow-up periods, and change in patient-reported measures of physical function, fatigue, and overall quality of life. ALLSTAR is a virtual, pragmatic randomized clinical trial powered to demonstrate whether gamification is superior to control in increasing physical activity in Black and Hispanic breast and prostate cancer survivors. Its results will have important implications for strategies to promote physical activity in survivors of breast and prostate cancer, specifically among minority populations. clinicaltrials.gov; https://clinicaltrials.gov/study/NCT05176756.

Long term risk of heart failure in adult cancer survivors: a systematic review and meta-analysis

Abstract Background Evaluation of the cardiotoxic effects from cancer is most commonly evaluated at the time of chemotherapy. Although cancer survivorship populations are rapidly expanding, there is a paucity of evidence regarding the frequency and causes of heart failure (HF) >5 years after cardiotoxic therapy. Objectives This systematic review sought to investigate the relationship between cardiotoxic cancer therapies and late-onset HF. Methods We searched the EMBASE and MEDLINE databases for studies reporting HF in adult survivors (≥50 years old), who were ≥5 years post-breast/lymphoma cancer therapy. A random effects model was used to examine the associations of HF. A meta-regression analysis was implemented to determine causes of heterogeneity. Results Thirteen papers were included in the review and meta-analysis (Figure 1), comprising 190,259 participants (mean age 53.5 years, 93% female). The risk of HF was increased (overall log risk-ratio 0.39 (95%CI (0.16-0.62)), (Figure 2). Cardiotoxic treatment, compared with cancer alone, provided a similar risk (log risk ratio of 0.38 [95% CI 0.02-0.77]). In the breast cancer population ratio (11 studies) the overall heart failure log risk was 0.41 [95% CI 0.13-0.69]). Although heterogeneity was significant (I²=77.17), this was explained by differences in patient characteristics; once multivariable analysis accounted for follow up (0.99, 95%CI (0.97-0.99), p=0.047), age (1.14, 95%CI (1.04-1.25), p=0.003) and hypertension (0.95, 95%CI (0.92-0.98), p<0.001), residual heterogeneity was low (I²=28.73). Conclusions HF is increased in adult cancer survivors, associated with cardiotoxic cancer therapy and standard risk factors. Consideration should be given for selective screening for HF in this at-risk population.Fig 1:Literature Search Flow DiagramFig 2:Incident HF in Cancer Survivors

Utility of mobile phone app-assisted screening for heart failure and heart stress in primary care

Abstract Background As heart failure (HF) still has a similar prognosis to some of the most common cancers, a timely diagnosis of HF is of paramount importance. We sought to determine whether a mobile phone app can facilitate screening for HF in primary care. Material and methods The national echocardiographic society conducted a multicenter screening programme for HF in which general practitioners from 13 primary care centres used a mobile phone app to decide whether patients without a prior HF diagnosis should be referred to one of the 6 university hospitals for transthoracic echocardiography (TTE) and N-terminal pro-B-type natriuretic peptide (NT-proBNP) testing. The app would recommend further testing (TTE and NT-proBNP) to patients with symptoms potentially associated with HF, atrial fibrillation, pathologic electrocardiogram (ECG), previous myocardial infarction or exposure to cardiotoxic cancer therapies, or at least two other risk factors listed in Figure (left panel). Patients with signs of HF were not eligible for the programme. The algorithms proposed in the 2021 ESC guidelines were used to diagnose HF across the entire spectrum of left ventricular ejection fraction (EF). Results Of the 930 screened outpatients (mean age 66±11 years, age range 21-91 years, 61% female), 318 symptomatic patients (34.2%) were diagnosed with new HF (Figure). HF with preserved (HFpEF) was diagnosed more frequently than HF with mildy reduced (HFmrEF) and reduced EF (HFrEF). Heart stress, defined as elevated plasma NT-proBNP in asymptomatic individuals with risk factors irrespective of the presence or absence of structural heart disease or cardiac dysfunction, was found in 22.3% (Figure, right panel). In multivariate regression analysis, advanced age, atrial fibrillation, pathological ECG, long-standing history of arterial hypertension and chronic kidney disease were independently associated with HF, while other risk factors were not (Figure, middle panel). Conclusions Screening in primary care based on symptoms and risk factors, facilitated by a mobile phone app, resulted in a new HF diagnosis in approximately one third of screened patients, with the majority of them having HFpEF. Recalibration of the referral criteria might further improve the performance of the app for screening purposes.

The BET protein inhibitor apabetalone (RVX-208) prevents doxorubicin-induced endothelial senescence

Abstract Background Accumulation of senescent endothelial cells (ECs) plays a pivotal role in cardiometabolic disorders and lifespan reduction(1). Yet, only a few senolytics are known to date, partly due to the poor grasp of the molecular mechanisms that control the senescence survival programme. Bromo-and extraterminal domain (BET) proteins, known epigenetic reader proteins, recognize acetylated histone tails and regulate gene transcription. RVX-208, an FDA-approved BET inhibitor, has shown to modulate transcriptional programs involved in inflammation, cancer, and renal disease(2). Yet, its potential role in EC senescence and cardio-oncology remains elusive. Purpose Our study aims to investigate whether pharmacological modulation of BET proteins by RVX-208 can mitigate doxorubicin-induced endothelial senescence. Methods Human aortic endothelial cells (HAECs) were exposed to different concentrations of Doxo (50nM-500nM) for 48 hours. Cell morphology changes, cell cycle arrest, senescence associated secreted phenotype (SASP) release, upregulation of SA-b gal activity, DNA damage response (gH2AX) and expression of p21, p16 and p53 were used as molecular markers of cellular senescence. Conditioned media was collected from Doxo-treated ECs and processed for molecular analyses or used for treatment of healthy, non-senescent ECs. To test whether RVX-208 exerts any senolytic or senomorphic effect, HAECs were treated with Doxo (100 nM) in presence or absence of RVX-208 (5mM-20mM) for 48 hrs. RNA-seq and proteomic profiling were performed in vehicle and Doxo-treated ECs. Results Doxo-treated ECs showed a dose-dependent increase in senescence markers (p16, p21 and p53) and DNA-damage response (gH2AX). FACS analysis revealed an accumulation of cells in G2/M phase in Doxo-treated ECs (100 nM). Of interest, treatment with RVX-208 (15mM) prevented the upregulation of senescent markers (p16, p21 and p53) while rescuing alterations in cell morphology and reducing the number of SA-b gal positive cells. RVX-208 prevented Doxo-induced upregulation of genes involved in inflammation, oxidative stress and mitochondrial dysfunction as shown by RNA-seq and proteomic analysis. Conditioned media from Doxo-treated ECs showed an enrichment of SASP-associated markers (IL6, CCL2, IL8, TIMP2 and PDGF-b) as shown by dot-blot arrays. Exposure of healthy ECs to conditioned media from senescent ECs recapitulated aging features. Notably, RVX-208 blunted the release of SASP markers (IL6, CCL2 and IL8) from Doxo-treated ECs. Mechanistically, we found enhanced BET protein occupancy (BRD4) with concomitant enrichment of activating chromatin marks (H3K27Ac and H3K4me) on the promoter of senescence genes COL1A2, CDKN1C and SESN3. Conclusion Targeting BET proteins with RVX-208 may offer a promising therapeutic strategy to prevent endothelial aging in cancer patients undergoing cardiotoxic therapies.

Feasibility and acceptability of a parent-child intervention to improve step count in childhood cancer survivors exposed to cardiotoxic therapy: The STEP UP for FAMILIES Study.

Late morbidity after childhood cancer may be mitigated by healthy lifestyle behaviors. We piloted a game-based, parent-child digital intervention to increase activity in sedentary survivors. Survivors aged 10-16 treated with cardiotoxic therapy and not meeting US physical activity guidelines were enrolled in a single-arm study with a parent. Following a 14-day run-in, participants chose a prespecified step goal and wore an accelerometer daily for 24weeks (12-week game-based intervention; 12-week follow-up). Participants completed the Acceptability of Intervention Measure (AIM) at 24weeks; a subset of dyads completed qualitative interviews. Among 129 eligible survivors, 27 enrolled (20.9% participation rate) with a parent. Four dyads were removed during the 14-day run-in period due to noncompliance. Among the 23 dyads who continued to the study, the tracker was worn for 95% of days during the 12-week intervention (95% confidence interval [CI]: 94-96) and 81% during the 12-week follow-up (95% CI: 79-82). Overall, the prespecified step goal was met for 64% (95% CI: 63-66) of days during the intervention and 37% (95% CI: 35-38) during the follow-up. At the end of study, 17/23 dyads responded to AIM; 82% of survivors and 94% of parents reported the intervention as acceptable. During qualitative interviews (n=5), dyads noted that they liked the accountability of the "buddy system," but would have liked more personalized goal-setting. Despite high ratings of acceptability among participants, difficulties with sustained adherence and retention were encountered in this parent-child gamification intervention. Alternate, tailored designs should be considered in the future.

Long-term risk of heart failure in adult cancer survivors: a systematic review and meta-analysis

BackgroundCancer survivors are at increased risk of heart failure (HF). While cardiotoxicity is commonly sought at the time of cancer chemotherapy, HF develops as a result of multiple ‘hits’ over...

Reproducibility and Repeatability in Focus: Evaluating LVEF Measurements with 3D Echocardiography by Medical Technologists.

Three-dimensional echocardiography (3DE) is currently the preferred method for monitoring left ventricular ejection fraction (LVEF) in cancer patients receiving potentially cardiotoxic anti-neoplastic therapy. In Denmark, however, the traditional standard for LVEF monitoring has been rooted in nuclear medicine departments utilizing equilibrium radionuclide angiography (ERNA). Although ERNA remains a principal modality, there is an emerging trend towards the adoption of echocardiography for this purpose. Given this context, assessing the reproducibility of 3DE among non-specialized medical personnel is crucial for its clinical adoption in such departments. To assess the feasibility of 3DE for LVEF measurements by technologists, we evaluated the repeatability and reproducibility of two moderately experienced technologists. They performed 3DE on 12 volunteers over two sessions, with a collaborative review of the results from the first session before the second session. Two-way intraclass correlation values increased from 0.03 to 0.77 across the sessions. This increase in agreement was mainly due to the recognition of false low measurements. Our findings underscore the importance of incorporating reproducibility exercises in the context of 3DE, especially when operated by technologists. Additionally, routine control of the acquisitions by physicians is deemed necessary. Ensuring these hurdles are adequately managed enables the adoption of 3DE for LVEF measurements by technologists.

Gastrointestinal Cancer Therapy and Cardiotoxicity.

Gastrointestinal cancers are a heterogenous group of cancers that share common risk factors with cardiovascular disease. Therapy for gastrointestinal cancers have improved cancer-specific outcomes at the cost of cardiotoxicity. The most common cardiotoxic therapies utilized in gastrointestinal cancers include conventional chemotherapy (including fluoropyrimidines and anthracyclines), targeted therapies including anti-vascular endothelial growth factor (VEGF) therapy and tyrosine kinase inhibitors (TKI), and immunotherapy. It is important for clinicians managing patients with gastrointestinal cancers to be aware of potential cardiotoxicity associated with these agents.

Sodium-glucose cotransporter 2 inhibitors and the cancer patient: from diabetes to cardioprotection and beyond.

Sodium-glucose cotransporter 2 inhibitors (SGLT2i), a new drug class initially designed and approved for treatment of diabetes mellitus, have been shown to exert pleiotropic metabolic and direct cardioprotective and nephroprotective effects that extend beyond their glucose-lowering action. These properties prompted their use in two frequently intertwined conditions, heart failure and chronic kidney disease. Their unique mechanism of action makes SGLT2i an attractive option also to lower the rate of cardiac events and improve overall survival of oncological patients with preexisting cardiovascular risk and/or candidate to receive cardiotoxic therapies. This review will cover biological foundations and clinical evidence for SGLT2i modulating myocardial function and metabolism, with a focus on their possible use as cardioprotective agents in the cardio-oncology settings. Furthermore, we will explore recently emerged SGLT2i effects on hematopoiesis and immune system, carrying the potential of attenuating tumor growth and chemotherapy-induced cytopenias.

EGFR-TKIs - induced cardiotoxicity in NSCLC: incidence, evaluation, and monitoring.

The advent of targeted drug therapy has greatly changed the treatment landscape of advanced non-small cell lung cancer(NSCLC), but the cardioxic side effects of targeted drug anti-cancer therapy seriously affect the prognosis of NSCLC, and it has become the second leading cause of death in cancer patients. Therefore, early identification of the cardiotoxic side effects of targeted drugs is crucial for the prevention and treatment of cardiovascular diseases. The cardiotoxic side effects that may be caused by novel targeted drugs epidermal growth factor receptor inhibitors, including thromboembolic events, heart failure, cardiomyopathy, arrhythmia and hypertension, are discussed, and the mechanisms of their respective adverse cardiovascular reactions are summarized, to provide useful recommendations for cardiac management of patients with advanced lung cancer to maximize treatment outcomes for lung cancer survivors. Clinicians need to balance the risk-benefit ratio between targeted therapy for malignant tumors and drug-induced cardiotoxicity, and evaluate and monitor TKIs-induced cardiotoxicity through electrocardiogram, cardiac imaging, biomarkers, etc., so as to remove the susceptibility risk factors as soon as possible and provide a reference for the clinical use of such drugs in the treatment of malignant tumors.

Timing of cardio-oncological rehabilitation and cardiorespiratory fitness in patients receiving cardiotoxic chemotherapy: a longitudinal observational study.

Anthracycline-based chemotherapy has well-known cardiotoxic effects, butmay also cause skeletal muscle myopathy and negatively affect cardiorespiratory fitness and quality of life. The effectiveness of exercise training in improving cardiorespiratory fitness and quality of life during chemotherapy is highly variable. We set out to determine how the effect of exercise training on cardiorespiratory fitness (primary outcome) and quality of life (secondary outcome) in cancer patients is affected by the type of therapy they receive (cardiotoxic therapy with or without anthracyclines; non-cardiotoxic therapy) and the timing of the exercise training (during or after therapy). Consecutive patients with cancer who participated in an exercise-based cardio-oncology rehabilitation programme at a university hospital in Switzerland between January 2014 and February 2022 were eligible. Patients were grouped based on chemotherapy (anthracycline vs non-anthracycline) and timing of exercise training (during vs after chemotherapy). Peak oxygen uptake (VO2) was assessed with cardiopulmonary exercise testing (n = 200), and quality of life with the Functional Assessment of Cancer Therapies questionnaire (n = 77). Robust linear models were performed for change in peak VO2including type and timing of cardiotoxic therapies, age, training impulse and baseline peak VO2; change in quality of life was analysed with cumulative linked models. In all patients with valid VO2(n = 164), median change in peak VO2from before to after exercise training was 2.3 ml/kg/min (range: -10.1-15.9). The highest median change in peak VO2was 4.1 ml/kg/min (interquartile range [IQR]: 0.7-7.7) in patients who completed exercise training during non-anthracycline cardiotoxic or non-cardiotoxic therapies, followed by 2.8 ml/kg/min (IQR: 1.2-5.3) and 2.3 ml/kg/min (IQR: 0.1-4.6) in patients who completed exercise training after anthracycline and after non-anthracycline cardiotoxic or non-cardiotoxic therapies, respectively. In patients who completed exercise training during anthracycline therapy, peak VO2decreased by a median of -2.1 ml/kg/min (IQR: -4.7-2.0). In the robust linear model, there was a significant interaction between type and timing of cancer treatment for anthracycline therapy, with greater increases in peak VO2when exercise training was performed after anthracycline therapy. For quality of life, higher baseline scores were negatively associated with changes in quality of life. In our cohort, the increase in cardiorespiratory fitness was diminished when exercise training was performed concurrently with anthracyclines. For patients with cardiotoxic treatments other than anthracyclines, cardiorespiratory fitness and quality of life was not associated with timing of exercise training.

Cardiac Dysfunction Among Breast Cancer Survivors: Role of Cardiotoxic Therapy and Cardiovascular Risk Factors.

Cardiac dysfunction is the leading cause of mortality among 10-year breast cancer survivors. Limited information regarding long-term risks of cardiac dysfunction after cardiotoxic therapy (anthracyclines, trastuzumab/pertuzumab, radiation) has precluded development of surveillance guidelines for the survivors. Patients with breast cancer who completed cardiotoxic therapy underwent echocardiographic screening every 2 years. New-onset cardiac dysfunction was defined as left ventricular ejection fraction (LVEF) <50% after cardiotoxic therapy initiation and included early- and late-onset cardiac dysfunction. We evaluated 2,808 echocardiograms in 829 breast cancer survivors; the median age at breast cancer diagnosis was 54.2 years (range, 20.3-86.3); the median follow-up was 8.6 years (1.8-39.8); 39.7% received anthracyclines, 16% received trastuzumab/pertuzumab, 6.2% received both anthracyclines and trastuzumab/pertuzumab, and 38.1% received radiation alone. The cumulative incidence of cardiac dysfunction increased from 1.8% at 2 years to 15.3% at 15 years from cardiotoxic therapy initiation. Multivariable Cox regression analysis identified the following risk factors: non-Hispanic Black race (hazard ratio [HR], 2.15 [95% CI], 1.37 to 3.38), cardiotoxic therapies (anthracyclines: HR, 2.35 [95% CI, 1.25 to 4.4]; anthracyclines and trastuzumab/pertuzumab: HR, 3.92 [95% CI, 1.74 to 8.85]; reference: left breast radiation alone), selective estrogen receptor modulators (HR, 2.0 [95% CI, 1.2 to 3.33]), and precancer hypertension (HR, 3.16 [95% CI, 1.63 to 6.1]). Late-onset cardiac dysfunction was most prevalent among anthracycline- and radiation-exposed patients; early-onset cardiac dysfunction was most prevalent among patients exposed to anthracyclines and trastuzumab/pertuzumab; equal prevalence of both early- and late-onset cardiac dysfunction was observed in trastuzumab-/pertuzumab-exposed patients. Adjusted longitudinal analyses revealed an annual decline in LVEF by 0.29% (P = .009) over 20 years from breast cancer diagnosis. These findings provide evidence to support echocardiographic surveillance for several years after cardiotoxic therapy and also suggest a need to examine the efficacy of management of cardiovascular risk factors to mitigate risk.

Immuno-related cardiac toxicity in patients with cancer: A prospective study applying multiparametric cardiac MRI.

e24014 Background: Since Immune checkpoint inhibitor (ICI) immunotherapy has emerged as a cornerstone of modern oncology, oncologists are facing a new spectrum of ‘immune-related adverse events’ (irAEs), potentially affecting every tissue and organ. ICI-induced symptomatic myocarditis occurs only in around 1% of ICI-treated patients (pts), but is fatal in 50% of cases. Methods: Pts undergoing ICI therapy at the Humanitas Cancer Center from May 2021 to December 2023 were prospectively recruited and assigned to three study groups: 1) ICI given as monotherapy (Mono) 2) ICI given in combination (Combo) 3) history of cardiac disease or two cardiological risk factors other than smoke (Cardio). Exclusion criteria were: previous exposure to any immunotherapy, combination with other cardiotoxic therapies, and acute (in the last 3 months) cardiac events. All pts underwent a complete cardiological assessment with clinical visit, 12-lead ECG, and multiparametric cardiac MRI (cMRI) at two time-points: prior initiation of the ICI therapy, and around 8 weeks later. Peripheral blood samples for immunophenotyping analyses were collected at the same time-points. cMRI scans were performed using a 1.5 Tesla scanner. Chi-square, Fisher exact and paired t-test were used to compare groups; all analyses were performed using SAS v9.4. Objectives of the study were: detection of subclinical cardiac damage and identification of groups of patients at major risk, who may benefit from cardiological pre- or/and on-treatment assessment. Results: We present data on the first 47 pts enrolled, diagnosed with a wide range of solid tumors, including 16 renal carcinoma, 11 melanoma and 3 NSCLC; 15 (32%), 16 (34%) and 16 (34%) pts were assigned to the Mono, Combo and Cardio group, respectively. Most pts (42, 89%) were treated with ICI for locally advanced/metastatic disease (26 as first-line therapy, 16 from second-line on), while 5 (11%) as adjuvant therapy. All pts received an anti-PD-(L)1, either as single agent (25, 53%) or in combination, with ICI plus a TKI being the most frequent combinatorial strategy (16; 34%). Overall, the cMRI analysis showed a statistically significant left ventricle ejection fraction (LVEF) reduction pre- versus post-ICI treatment (p &lt; 0.001), with 18 (38%) pts experiencing a loss of &gt; 3 points of LVEF. No statistically significant differences in LVEF reduction were observed considering the three different groups (p = 0.6), tumor types (p = 0.2), or occurrence of any grade non-cardiological irAEs (p = 0.6). Conclusions: Our study was able to show a statistically significant reduction in LVEF, with more than 3% LVEF loss in a clinically significant proportion of ICI-treated patients (18; 38%), not selected for suspected cardiac symptoms, warranting prospective evaluation to eventually identify pts at higher risk. The trial is continuing prospective enrollment and immunophenotyping analyses are ongoing.

Unveiling the influence of SGLT2 inhibitors on clinical outcomes in patients with cancer with therapy-related cardiac dysfunction: A meta-analysis and systemic review.

e24003 Background: Cancer patients undergoing chemotherapy suffer from a variable degree of cancer therapy–related cardiac dysfunction and heart failure (HF). It is known that sodium glucose co-transporter 2 (SGLT2) inhibitors improve outcomes in patients with HF independent of diabetes mellitus and left ventricular ejection fraction; our study aims to investigate the potential benefits of SGLT2 inhibitory therapy specifically in cancer patients undergoing chemotherapy. Methods: We performed an electronic search on PubMed, Embase, and Cochrane, from the inception of databases till January 29, 2024, to identify all the articles that compared the use of SGLT2 inhibitors in adult (≥18 years) with type 2 diabetes mellitus and exposure to cardiotoxic antineoplastic therapy, subsequently diagnosed with cardiomyopathy, heart failure, or LVEF &lt; 40%. The data was extracted and pooled using a random effects model to calculate the odds ratio (OR) with a respective 95% confidence interval (CI). R software (v.4.3) was used for all statistical analyses. Results: Our search identified three observational studies with a total of 3,164 patients (SGLT2- inhibitor group: 1,550; Control group: 1,614). We found that the use of SGLT2 inhibitors was associated with a lower risk of all-cause mortality (OR: 0.25 [0.20, 0.31]; I2 = 16%; p &lt; 0.001), hospitalizations from heart failure (OR: 0.25 [0.10, 0.62]; I2 = 0%; p = 0.003), and acute exacerbation of heart failure (OR: 0.35 [0.27, 0.47]; I2 = 0%; p &lt; 0.001). Conclusions: Our findings suggest a favorable association between the use of SGLT2 inhibitors and reduced mortality, as well as improved cardiac clinical outcomes in cancer patients undergoing chemotherapy. However, further validation through large-scale studies and randomized controlled trials across diverse malignancies is warranted to establish the efficacy of these drugs. [Table: see text]

Therapy-naïve malignancy causes cardiovascular disease: a state-of-the-art cardio-oncology perspective.

Cardiovascular disease (CVD) and cancer are the leading causes of mortality worldwide. Although generally thought of as distinct diseases, the intersectional overlap between CVD and cancer is increasingly evident in both causal and mechanistic relationships. The field of cardio-oncology is largely focused on the cardiotoxic effects of cancer therapies (e.g., chemotherapy, radiation). Furthermore, the cumulative effects of cardiotoxic therapy exposure and the prevalence of CVD risk factors in patients with cancer lead to long-term morbidity and poor quality of life in this patient population, even when patients are cancer-free. Evidence from patients with cancer and animal models demonstrates that the presence of malignancy itself, independent of cardiotoxic therapy exposure or CVD risk factors, negatively impacts cardiac structure and function. As such, the primary focus of this review is the cardiac pathophysiological and molecular features of therapy-naïve cancer. We also summarize the strengths and limitations of preclinical cancer models for cardio-oncology research and discuss therapeutic strategies that have been tested experimentally for the treatment of cancer-induced cardiac atrophy and dysfunction. Finally, we explore an adjacent area of interest, called "reverse cardio-oncology," where the sequelae of heart failure augment cancer progression. Here, we emphasize the cross-disease communication between malignancy and the injured heart and discuss the importance of chronic low-grade inflammation and endocrine factors in the progression of both diseases.

Colorectal cancer and the heart: Uncovering the beat of racial disparities in MACCE.

1611 Background: Due to its high prevalence, colorectal cancer (CRC) forms a considerable burden on the healthcare system. Advancements in treatment modalities like immunotherapy have led to significant improvement in the 5-year survival. This, along with the cardiotoxic therapy regimens results in a remarkable incidence of major cardiovascular and cerebrovascular events (MACCE). Thus, it becomes imperative to address the intricacies of factors including racial disparities in MACCE, as these aid with facilitating equitable management of all CRC patients. Methods: Using ICD-10 codes, patients with CRC were identified from National Inpatient Sample 2019 database. We included all-cause in-hospital mortality (ACIHM), acute myocardial infarction (AMI), atrial fibrillation (AF), cerebrovascular accident (CVA), and sudden cardiac death (SCD) as MACCE for the outcomes. Baseline characteristics including demographics, comorbidities; and MACCE outcomes were studied using chi-square for categorical or ANOVA for continuous data (statistical significance determined as p-value &lt; 0.05) and results were stratified based on patient’s races. Results: A total sample patient population of 171,695 patients with a diagnosis of CRC were identified of which 70.71% (121,410) were White, 13.85% (23,790) were Black, 9.15% (15,720) were Hispanic, 3.23% (5,555) were Asian/Pacific Islander, 0.5% (840) were Native American, and 2.55% (4380) belonged to Other races. Substantial differences in the prevalence of comorbidities were noted with hypertension (46.32%) and renal failure (24.74%) being more common in Black patients, diabetes mellitus (37.5%) in Native American patients, and dyslipidemia (37.89%) in White patients. Upon comparison with White patients, the ACIHM was higher in Black patients with adjusted odds ratio (aOR) of 1.23 (95% CI 1.057-1.432, p = 0.007) and Asian/Pacific Islander patients with aOR of 1.359 (1.014-1.823, p = 0.04). While AMI was found to be lower in all races, as compared to White patients, AF was remarkably higher in all races. CVA was higher in Black patients as compared to White patients with aOR of 1.626 (95% CI 1.401-1.886, p &lt; 0.001). SCD was substantially higher in Black patients with aOR 2.059 (95% CI 1.478-2.869, p &lt; 0.001), and in Hispanic patients with aOR 1.743 (95% CI 1.1-2.761, p = 0.018), when compared to White patients. Conclusions: The study noted higher prevalence of MACCE across the board with poorer outcomes in non-White populations, which highlights the urgent need for resource allocation to improve outcomes. This has to be done in pre and post cancer treatment patients, especially in high risk populations. Additionally, the role of cardio-oncology service at every stage of management of CRC appears to be crucial.