Doxorubicin (DOX) is the most effective chemotherapeutic for breast cancer, but it is usually associated with severe cardiotoxicity. Further investigation to alleviate its side effects is essential. The present study investigated the mechanism of the cross-organ communication between tumors and the heart and potential intervention targets. Morphological bubble-like protrusions were observed in both adult murine ventricular cardiomyocytes (AMVCs) and human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) cocultured with breast cancer cells (BCCs), along with elevated expression of pyroptosis-related proteins. Exosomes (EXOs) from DOX-treated BCCs aggravated DOX-induced cardiotoxicity (DOXIC) in an orthotopic mouse model of breast cancer. Blocking miRNAs by knocking down Rab27a or inhibiting the release of EXOs in cancer tissue by Dicer enzyme knockout attenuated this additional injury effect. Exosomal miRNA sequencing revealed that miR-216a-5p is especially upregulated in EXOs from DOX-induced BCCs. Mechanistically, miR-216a-5p was upregulated by enhanced transcription mediated by DOX-induced AMP-dependent transcription factor 3 (ATF3) and packaged into EXOs by splicing factor 3b subunit 4 (SF3B4) in BCCs. Itchy E3 ubiquitin-protein ligase (ITCH) was identified as a novel downstream target mRNA of miR-216a-5p. ITCH negatively mediated thioredoxin-interacting protein (TXNIP) ubiquitination to activate the NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome pathway, ultimately leading to cardiomyocyte pyroptosis. Our findings revealed novel cross-organ pathogenic communication between breast cancer and the heart through the exosomal miR-216a-5p-mediated ITCH/TXNIP/NLRP3 pathway, which drives cardiomyocyte pyroptosis. These findings suggest that targeting myocardial miR-216a-5p or blocking harmful EXOs from breast cancer is a potential therapeutic strategy for alleviating DOXIC.

Cardiovascular toxicity is a significant side effect of breast cancer treatment and has emerged as a leading cause of non-tumor-related deaths among breast cancer survivors, emphasizing the critical need for effective monitoring and management of these complications. As breast cancer remains the most prevalent cancer among women, advancements in survival rates have been achieved through treatments such as chemotherapy, targeted therapy, endocrine therapy, immunotherapy, and radiotherapy. This review provides a comprehensive understanding of the cardiovascular toxicity mechanisms associated with both established and emerging breast cancer therapies, identifies potential therapeutic targets and monitoring strategies, and highlights key deficiencies and challenges in the field. By offering insights into the early detection, prevention, and management of cardiovascular complications, this review aims to guide future research directions and clinical practices, ultimately improving outcomes for breast cancer patients.

Breast cancer survivors (BCS) face a higher risk of cardiovascular disease (CVD) due to treatment-related cardiotoxicity and pre-existing conditions. We investigated how post-diagnosis weight changes and obesity impact CVD risk in this population.

Using the Korean National Health Insurance Service database (2010-2019), BCS without previous history of CVD were enrolled. Weight change was determined using standardized anthropometric protocols during biennial health examinations pre- and post-diagnosis. The primary outcome was incident CVD, a composite of myocardial infarction (MI) and ischemic stroke. Adjusted hazard ratios (aHRs) and confidence intervals (CIs) were estimated, accounting for cardiovascular risk factors, cancer treatments, and sociodemographic variables.

During a mean follow-up of 3.70 years among the 42,547 BCS (mean [SD] age 53.4 [9.4] years), substantial weight gain (> 10%) was associated with increased CVD risk (aHR 1.66, 95% CI 1.05-2.62) and MI risk (aHR 1.83, 95% CI 1.01-3.33) compared to those who maintained their weight. The association between change in obesity status and CVD risk was not significant. Among BCS with sustained obesity, CVD risk was more pronounced in younger survivors (< 50 years) (aHR 3.58, 95% CI 1.94-6.61), and in those using tamoxifen (aHR 1.74, 95% CI 1.11-2.75) (P-interactions < 0.05).

Our findings suggest that BCS who experience substantial weight gain post-diagnosis have an increased risk of CVD. Further intervention studies (e.g., GLP-1 agonist) are needed to ascertain the effects of weight changes on CVD risks in BCS.

Breast cancer survivors experience numerous chronic symptoms linked to autonomic dysfunction including anxiety, stress, insomnia, menopausal symptoms, and cognitive impairment. Effective non-pharmacological solutions to address these are currently lacking.

Our three-armed longitudinal randomized controlled trial assessed the effectiveness of a 4-week remote smartphone-based heart rate variability biofeedback intervention which involved daily paced breathing at 6 breaths p/min; active (12 breaths p/min) and waitlist controls were included. Heart rate variability and self-reported cancer-related symptoms were assessed at baseline, post-, and 6 months-post intervention. Participants were 60 UK-based women with primary breast cancer history (6 to 60 months post-active treatment).

The intervention group showed significant increases in low-frequency heart rate variability over time (F (4, 103.89) = 2.862, p = 0.027, d = 0.33), long-lasting improvement in sleep quality (F (4, 88.04) = 4.87, p = 0.001, d = 0.43) and cessations in night sweats (X2 (2, N = 59) = 6.44, p = 0.04, Cramer's V = 0.33), and reduced anxiety post-intervention compared to the active and waitlist controls (F (4, 82.51) = 2.99, p = 0.023, d = 0.44). Other findings indicated that the intervention and active control participants reported lasting improvements in cognitive function, fatigue, and stress-related symptoms (all ps < 0.05). The waitlist group reported no symptom changes across time.

Heart rate variability biofeedback is a feasible intervention for addressing diverse chronic symptoms commonly reported by breast cancer survivors.

Cancer patients are at an increased risk for the incidence and complications of acute myocardial infarction (AMI) due to shared risk factors and treatment-related adverse effects. Mortality trends for AMI-related deaths in adult cancer patients in the U.S. remain unexplored.

This study used CDC WONDER data for death certificates from 1999 to 2020, identifying U.S. adults (≥25 years) with cancer (ICD-10: C00-D49) who died of AMI (ICD-10: I21) as the underlying cause. Age-adjusted mortality rates (AAMRs) and annual percent changes (APCs) were calculated and stratified by gender, age, race, and geographic location.

Between 1999 and 2020, there were 109,462 AMI-related deaths in adult cancer patients. The AAMR decreased from 4.3 per 100,000 in 1999 to 1.4 in 2020. A significant decline occurred from 1999 to 2015 (APC: 6.65; 95 % CI: 6.95 to -6.40; p < 0.001), followed by a stable trend from 2015 to 2020 (APC: 1.36; 95 % CI: 2.69 to 0.91; p = 0.152). Men had higher AAMRs than women (3.5 vs. 1.5). AAMRs were highest in older adults (10.5) compared to middle-aged (0.7) and young adults (0.1). Racial disparities showed the highest AAMRs in non-Hispanic (NH) Black patients (2.7), followed by NH Whites (2.4), NH American Indian/Alaska Native (1.6), Hispanic/Latino (1.3), and NH Asian/Pacific Islander (1.1). Non-metropolitan areas had higher AAMRs than metropolitan areas (2.8 vs. 2.2).

This analysis highlights a significant decline in AMI-related mortality among cancer patients in the U.S., with persistent disparities by gender, age, race and geographical location.

Baseline cardiovascular toxicity risk stratification is critical in cardio-oncology. The Heart Failure Association (HFA) and International Cardio-Oncology Society (ICOS) score aims to assess this risk but lacks real-life validation. This study validates the HFA-ICOS score for anthracycline-induced cardiovascular toxicity.

Anthracycline-treated patients in the CARDIOTOX registry (NCT02039622) were stratified by the HFA-ICOS score. The primary endpoint was symptomatic or moderate to severe asymptomatic cancer therapy-related cardiac dysfunction (CTRCD), with all-cause mortality and cardiovascular mortality as secondary endpoints.

The analysis included 1066 patients (mean age 54 ± 14 years; 81.9% women; 24.5% ≥65 years). According to the HFA-ICOS criteria, 571 patients (53.6%) were classified as low risk, 333 (31.2%) as moderate risk, 152 (14.3%) as high risk, and 10 (0.9%) as very high risk. Median follow-up was 54.8 months (interquartile range 24.6-81.8). A total of 197 patients (18.4%) died, and 718 (67.3%) developed CTRCD (symptomatic: n = 45; moderate to severe asymptomatic: n = 24; and mild asymptomatic: n = 649). Incidence rates of symptomatic or moderate to severe symptomatic CTRCD and all-cause mortality significantly increased with HFA-ICOS score [hazard ratio 28.74, 95% confidence interval (CI) 9.33-88.5; P < .001, and hazard ratio 7.43, 95% CI 3.21-17.2; P < .001) for very high-risk patients. The predictive model demonstrated good calibration (Brier score 0.04, 95% CI 0.03-0.05) and discrimination (area under the curve 0.78, 95% CI 0.70-0.82; Uno's C-statistic 0.78, 95% CI 0.71-0.84) for predicting symptomatic or severe/moderate asymptomatic CTRCD at 12 months.

The HFA-ICOS score effectively categorizes patients by cardiovascular toxicity risk and demonstrates strong predictive ability for high-risk anthracycline-related cardiovascular toxicity and all-cause mortality.

The heart depends critically on continuous blood supply, but it is unknown whether cancer itself affects myocardial blood flow (MBF). This study investigated MBF in cancer patients and cardiac morphology in a cancer mice model. MBF was quantified with [15O]H2O positron emission tomography at rest in recently diagnosed breast cancer patients and age-matched female controls, and additionally during 10-min exercise in the cancer patients. Cardiac morphological changes were analyzed with a breast cancer mouse model and control mice without tumors. Resting MBF was similar in cancer patients and controls. MBF increased significantly during exercise in cancer patients, and exercising MBF correlated positively with cancer grade. In the mouse model, cancer did not affect heart weight, cardiomyocyte size, myocardial capillary density, or capillary-to-myocyte size ratio. Thus, resting MBF in humans or myocardial capillarity in mice appears not to be affected by breast cancer. The exercise-induced MBF increase in cancer patients with higher histologic grade requires further investigations.

The causal relationship of breast cancer (BC) with cardiovascular disease (CVD) and the underlying mediating pathways remains elusive. Our study endeavors to investigate the causal association between BC and CVD, with a focus on identifying potential metabolic mediators and elucidating their mediation effects in this causality.

In this study, we conducted two-sample Mendelian randomization (MR) to estimate the causal effect of BC (overall BC, ER+ BC, ER- BC) from the Breast Cancer Association Consortium (BCAC) on CVD including coronary heart disease (CHD), hypertensive heart disease (HHD), ischaemic heart disease (IHD), and heart failure (HF) from the FinnGen consortium. Then, we used two-step MR to evaluate 18 metabolic mediators of the association and calculate the mediated proportions.

Genetically predicted ER+ BC was causally associated with an increased risk of CVD including CHD (OR = 1.034, 95% CI: 1.004-1.065, p = 0.026), HHD (OR = 1.061, 95% CI: 1.002-1.124, p = 0.041), IHD (OR = 1.034, 95% CI: 1.007-1.062, p=0.013), and HF (OR = 1.055, 95% CI: 1.013-1.099, p = 0.010), while no causality was observed for overall BC and ER- BC. Furthermore, high-density lipoprotein cholesterol (HDL-C) was identified as a mediator of the association between ER+BC and CVD, including CHD (with 15.2% proportion)) and IHD (with 15.5% proportion), respectively.

This study elucidates the potential causal impact of ER+ BC on subsequent risk of CVD, including CHD, HHD, IHD, and HF. We also outline the metabolic mediator HDL-C as a priority target for preventive measures to reduce excessive risk of CVD among patients diagnosed with ER+BC.

Modern cancer therapies greatly improve clinical outcomes for both early and advanced breast cancer patients. However, these advances have raised concerns about potential short- and long-term toxicities, including cardiovascular toxicities. Therefore, understanding the common risk factors and underlying pathophysiological mechanisms contributing to cardiovascular toxicity is essential to ensure best breast cancer outcomes. While cardio-oncology has emerged as a sub-speciality to address these challenges, it is essential that all cardiologists recognize and understand the cardiovascular consequences of cancer therapy. This review aims to provide a comprehensive overview of the potential adverse cardiovascular effects associated with modern breast cancer therapies. A preventive, diagnostic, and therapeutic workflow to minimize the impact of cardiovascular toxicity on patient outcomes is presented. Key aspects of this workflow include regular monitoring of cardiovascular function, early detection and management of cancer therapy-related cardiovascular toxicities, and optimization of cardiovascular risk factor control. By highlighting the gaps in knowledge in some areas, this review aims to emphasize the critical role of cardio-oncology research in ensuring the holistic well-being of patients with breast cancer.

Understanding the specific needs of cancer survivors is essential for healthcare policy. In Italy, dedicated studies are lacking, so we aimed to investigate the physical, mental, social, and health difficulties encountered by these patients.

We conducted a cross-sectional study on breast or colorectal cancer survivors (people 5+ years free from it and its treatments) using an ad hoc survey including validated questionnaires (Grauer-Palombi, SF-36, PREDIMED). Participants were recruited within the Oncology Unit of the "Policlinico Tor Vergata", Italy.

A total of 62 patients (80.6% females; years range: 37-87) agreed to be interviewed. A profile of cancer survivors was drafted: an overaged person with multiple co-morbidities, not well-nourished, adhering to the Mediterranean diet, reporting critical conditions as for physical and functional status. The mean number of co-morbidities was 3.6 ± 2.4 SD, with a statistically significant difference between age groups (under and over 65). Compared to the general population, the sample showed more frailties, especially when >65. The risk of having multimorbidity (four or more co-morbidities) significantly increased in those over 65 (OR: 4.72; CI: 1.43-15.59).

There is an urgent need for survivorship care planning for the patient-centered continuum of care. Assessing and monitoring their specific needs will help propose appropriate and tailored responses.

Recent breakthroughs in human genetics and in information technologies have markedly expanded our understanding at the molecular level of the response to drugs, i.e., pharmacogenetics (PGx), across therapy areas. This review is restricted to PGx for cardiovascular (CV) drugs. First, we examined the PGx information in the labels approved by regulatory agencies in Europe, Japan, and North America and related recommendations from expert panels. Out of 221 marketed CV drugs, 36 had PGx information in their labels approved by one or more agencies. The level of annotations and recommendations varied markedly between agencies and expert panels. Clopidogrel is the only CV drug with consistent PGx recommendation (i.e., "actionable"). This situation prompted us to dissect the steps from discovery of a PGx association to clinical translation. We found 101 genome-wide association studies that investigated the response to CV drugs or drug classes. These studies reported significant associations for 48 PGx traits mapping to 306 genes. Six of these 306 genes are mentioned in the corresponding PGx labels or recommendations for CV drugs. Genomic analyses also highlighted the wide between-population differences in risk allele frequencies and the individual load of actionable PGx variants. Given the high attrition rate and the long road to clinical translation, additional work is warranted to identify and validate PGx variants for more CV drugs across diverse populations and to demonstrate the utility of PGx testing. To that end, pre-emptive PGx combining genomic profiling with electronic medical records opens unprecedented opportunities to improve healthcare, for CV diseases and beyond. SIGNIFICANCE STATEMENT: Despite spectacular breakthroughs in human molecular genetics and information technologies, consistent evidence supporting PGx testing in the cardiovascular area is limited to a few drugs. Additional work is warranted to discover and validate new PGx markers and demonstrate their utility. Pre-emptive PGx combining genomic profiling with electronic medical records opens unprecedented opportunities to improve healthcare, for CV diseases and beyond.

Over the years, strides in colon cancer detection and treatment have boosted survival rates; yet, post-colon cancer survival entails cardiovascular disease (CVD) risks. Research on CVD risks and acute cardiovascular events in colorectal cancer survivors has been limited.

To compare the CVD risk and adverse cardiovascular outcomes in current colon cancer survivors compared to a decade ago.

We analyzed 2007 and 2017 hospitalization data from the National Inpatient Sample, studying two colon cancer survivor groups for CVD risk factors, mortality rates, and major adverse events like pulmonary embolism, arrhythmia, cardiac arrest, and stroke, adjusting for confounders via multivariable regression analysis.

Of total colon cancer survivors hospitalized in 2007 (n = 177542) and 2017 (n = 178325), the 2017 cohort often consisted of younger (76 vs 77 years), male, African-American, and Hispanic patients admitted non-electively vs the 2007 cohort. Furthermore, the 2017 cohort had higher rates of smoking, alcohol abuse, drug abuse, coagulopathy, liver disease, weight loss, and renal failure. Patients in the 2017 cohort also had higher rates of cardiovascular comorbidities, including hypertension, hyperlipidemia, diabetes, obesity, peripheral vascular disease, congestive heart failure, and at least one traditional CVD (P < 0.001) vs the 2007 cohort. On adjusted multivariable analysis, the 2017 cohort had a significantly higher risk of pulmonary embolism (PE) (OR: 1.47, 95%CI: 1.37-1.48), arrhythmia (OR: 1.41, 95%CI: 1.38-1.43), atrial fibrillation/flutter (OR: 1.61, 95%CI: 1.58-1.64), cardiac arrest including ventricular tachyarrhythmia (OR: 1.63, 95%CI: 1.46-1.82), and stroke (OR: 1.28, 95%CI: 1.22-1.34) with comparable all-cause mortality and fewer routine discharges (48.4% vs 55.0%) (P < 0.001) vs the 2007 cohort.

Colon cancer survivors hospitalized 10 years apart in the United States showed an increased CVD risk with an increased risk of acute cardiovascular events (stroke 28%, PE 47%, arrhythmia 41%, and cardiac arrest 63%). It is vital to regularly screen colon cancer survivors with concomitant CVD risk factors to curtail long-term cardiovascular complications.

Improvements in cancer treatment have led to more people living with and beyond a cancer diagnosis but survivors may have increased health problems as they age. The purpose of this review is to critically evaluate population data exploring incidence of late effects for cancer survivors.

18 studies were identified between 2013 and 2023 that explored the impact on survivors' physical and emotional health. Patients who had been treated at least 2 years previously for cancer had significant cardiovascular risk factors compared with age-matched controls. Women with breast cancer were more likely to have cardiovascular disease, including hypertension, arrythmias and congestive heart failure. This was associated with anthracyclines and/or trastuzumab as part of systemic anti-cancer therapy. Survivors of colorectal cancer were three times more likely to have acute kidney injury than age-matched controls. Stress and mood disorders were higher in survivors of testicular cancer and prostate cancer.

Population studies are important to identify the 'real world' consequences of cancer and its treatment beyond clinical trials. Knowledge is critical for managing an ageing cancer population. Data to personalise cancer survivorship care, not only helps determine potential health risks, but can improve secondary prevention, emotional health, recovery, and long-term outcomes.

Cardiotoxicity among breast cancer survivors is associated with chemotherapy and radiation therapy. The risk of cardiovascular disease (CVD) among Asian, Native Hawaiian and Pacific Islander (ANHPI) breast cancer survivors in the United States is unknown.

We used the SEER-Medicare linked database to estimate the risk of CVD among older breast cancer survivors. International Classification of Disease diagnosis codes were used to identify incident CVD outcomes. Cox proportional hazards models were used to estimate HRs and 95% confidence intervals (CI) comparing ANHPI with Non-Hispanic White (NHW) patients with breast cancer for CVD, and among ANHPI race and ethnicity groups.

A total of 7,122 ANHPI breast cancer survivors and 21,365 NHW breast cancer survivors were identified. The risks of incident heart failure and ischemic heart disease were lower among ANHPI compared with NHW breast cancer survivors (HRheart failure, 0.72; 95% CI, 0.61-0.84; HRheart disease, 0.74; 95% CI, 0.63-0.88). Compared with Japanese patients with breast cancer, Filipino, Asian Indian and Pakistani, and Native Hawaiian breast cancer survivors had higher risks of heart failure. ischemic heart disease and death. Among ANHPI breast cancer survivors, risk factors for heart failure included older age, higher comorbidity score, distant cancer stage and chemotherapy.

Our results support heterogeneity in CVD outcomes among breast cancer survivors among ANHPI race and ethnicity groups. Further research is needed to elucidate the disparities experienced among ANHPI breast cancer survivors.

Filipino, Asian Indian and Pakistani, and Native Hawaiian patients with breast cancer had higher risks of heart failure, ischemic heart disease and death among ANHPI patients with breast cancer.

Cardiovascular disease is a major cause of mortality among oncologic patients. As cancer therapies continue to evolve and advance, cancer survival rates have been increasing and so has the burden of cardiovascular disease within this population. For this reason, cardio-oncology plays an important role in promoting multidisciplinary care with the primary care provider, oncology, and cardiology. In this review, we discuss the roles of different providers, strategies to monitor patients receiving cardiotoxic therapies, and summarize cancer therapy class-specific toxicities. Continued collaboration among providers and ongoing research related to cardiotoxic cancer therapies will enable patients to receive maximal, evidence-based, comprehensive care.

Reduced cognition is often reported by breast cancer patients and survivors, but the mechanisms for this decline are yet to be determined. We compared the differences in cerebrovascular function and cognition in breast cancer survivors (n = 15) and cancer-free women (n = 15) matched by age and body mass index. Participants undertook anthropometric, mood, cardiovascular, exercise performance, strength, cerebrovascular, and cognitive measurements. Transcranial Doppler ultrasound was used to measure the cerebrovascular responsiveness (CVR) to physiological (hypercapnia; 5% carbon dioxide) and psychological stimuli. Breast cancer survivors had a lower CVR to hypercapnia (21.5 ± 12.8 vs 66.0 ± 20.9%, P < 0.001), CVR to cognitive stimuli (15.1 ± 1.5 vs 23.7 ± 9.0%, P < 0.001) and total composite cognitive score (100 ± 12 vs. 113 ± 7, P = 0.003) than cancer-free women. These parameters remained statistically different between the groups following adjustments for covariates using an analysis of co-variance. We observed significant correlations between multiple measures and exercise capacity the only variable positively correlated to all primary measures (CVR to hypercapnia, r = 0.492, P = 0.007; CVR to cognitive stimuli r = 0.555, P = 0.003; and total composite cognitive score, r = 0.625, P < 0.001). In this study, breast cancer survivors had lower cerebrovascular and cognitive function than age-matched cancer-free women, which may be attributable to the effects of cancer and cancer treatment on brain health.