Navigating cancer therapy induced cardiotoxicity: From pathophysiology to treatment innovations.

Every year, more than a million people in the United States undergo chemotherapy or radiation therapy for cancer, as estimated by the CDC. While chemotherapy has been an instrumental tool for treating cancer, it also causes severe adverse effects. The more commonly acknowledged adverse effects include hair loss, fatigue, and nausea, but a more severe and longer lasting side effect is cardiotoxicity. Cardiotoxicity, or heart damage, is a common complication of cancer treatments. It can range from mild to severe, and it can affect some patients temporarily or others permanently, even after they are cured of cancer. Dexrazoxane is the only FDA-approved drug for treating anthracycline induced cardiotoxicity, but it also has drawbacks and adverse effects. There is no other type of chemotherapy induced cardiotoxicity that has an approved treatment option. In this review, we discuss the pathophysiology of chemotherapeutic-induced cardiotoxicity, methods and guidelines of diagnosis, methods of treatment and mitigation, and current drug delivery approaches in therapeutic development.

New Insights in the Era of Clinical Biomarkers as Potential Predictors of Systemic Therapy-Induced Cardiotoxicity in Women with Breast Cancer: A Systematic Review.

Cardiotoxicity induced by breast cancer therapies is a potentially serious complication associated with the use of various breast cancer therapies. Prediction and better management of cardiotoxicity in patients receiving chemotherapy is of critical importance. However, the management of cancer therapy-related cardiac dysfunction (CTRCD) lacks clinical evidence and is based on limited clinical studies. AIM: To provide an overview of existing and potentially novel biomarkers that possess a promising predictive value for the early and late onset of CTRCD in the clinical setting. METHODS: A systematic review of published studies searching for promising biomarkers for the prediction of CTRCD in patients with breast cancer was undertaken according to PRISMA guidelines. A search strategy was performed using PubMed, Google Scholar, and Scopus for the period 2013-2023. All subjects were >18 years old, diagnosed with breast cancer, and received breast cancer therapies. RESULTS: The most promising biomarkers that can be used for the development of an alternative risk cardiac stratification plan for the prediction and/or early detection of CTRCD in patients with breast cancer were identified. CONCLUSIONS: We highlighted the new insights associated with the use of currently available biomarkers as a standard of care for the management of CTRCD and identified potentially novel clinical biomarkers that could be further investigated as promising predictors of CTRCD.

H2S Donors with Cytoprotective Effects in Models of MI/R Injury and Chemotherapy-Induced Cardiotoxicity.

Hydrogen sulfide (H2S) is an endogenous signaling molecule that greatly influences several important (patho)physiological processes related to cardiovascular health and disease, including vasodilation, angiogenesis, inflammation, and cellular redox homeostasis. Consequently, H2S supplementation is an emerging area of interest, especially for the treatment of cardiovascular-related diseases. To fully unlock the medicinal properties of hydrogen sulfide, however, the development and refinement of H2S releasing compounds (or donors) are required to augment its bioavailability and to better mimic its natural enzymatic production. Categorizing donors by the biological stimulus that triggers their H2S release, this review highlights the fundamental chemistry and releasing mechanisms of a range of H2S donors that have exhibited promising protective effects in models of myocardial ischemia-reperfusion (MI/R) injury and cancer chemotherapy-induced cardiotoxicity, specifically. Thus, in addition to serving as important investigative tools that further advance our knowledge and understanding of H2S chemical biology, the compounds highlighted in this review have the potential to serve as vital therapeutic agents for the treatment (or prevention) of various cardiomyopathies.

Reintroduction of 5-Fluorouracil Post-cardiac Arrest Secondary to Chemotherapy-Induced Cardiotoxicity.

5-fluorouracil (5-FU) has been known to have cardiotoxic side effects, including coronary vasospasm, myocardial infarctions, heart failure, arrhythmias, and cardiac arrest. These cases have been reported in patients with either known coronary disease or known risk factors. In cases of acute cardiotoxicity, cessation of fluoropyrimidines is recommended, and reintroduction of the medication is generally avoided. We present a case of a young patient with no known risk factors for coronary disease, who presented with an acute cardiac arrest suspected secondary to vasospasm from the administration of 5-FU for the treatment of rectal cancer and was successfully maintained on treatment with 5-FU post-arrest after transitioning from an infusion to bolus administration.

Cytarabine-Induced Bradycardia: A Case Report.

Cardiotoxicity is damage to the heart muscle, which affects its function. Chemotherapy is known to cause cardiotoxicity along with many other medications and etiologies. Many chemotherapeutic cocktails are known to be associated with cardiotoxicities, such as taxane and cisplatin. Patients might have arrhythmias, severe bradycardia, cardiomyopathy, and even cardiac arrest, so precautions are taken when such medications are started. This report presents a patient who developed severe symptomatic bradycardia after receiving idarubicin and cytarabine and was managed conservatively, along with a literature review of this entity.

Cancer and cardiovascular disease: can understanding the mechanisms of cardiovascular injury guide us to optimise care in cancer survivors?

Cancer and cardiovascular disease (CVD) are the leading causes of morbidity and mortality. Therefore, CVD deaths in cancer survivors remain a major challenge in improving cancer outcomes, especially in low and middle income countries (LMICs). Cancer and CVD share many common risk factors, both modifiable risk factors (obesity, diabetes and smoking) and non-modifiable factors such as inflammation. Additionally, some cancer therapies are associated with cardiac toxicity. These mechanisms drive increased CVD outcomes in cancer survivors, and understanding this relationship allows us to target therapies to combat such risks. Several commonly used pharmacotherapies for CVD demonstrate promise in cancer survivors for both primary and secondary prevention. Beta blockers and Angiotensin converting enzyme (ACE)-inhibitors have been shown in several studies to improve left ventricular ejection fraction (LVEF) in patients with already established LVEF decline following cancer therapy. Statin use during chemotherapy was associated with lower risk of heart failure and smaller declines in LVEF. Recent studies into the effects of anti-inflammatory medications on cardiovascular events in the non-cancer population have demonstrated promising results and may prove to be an area of further investigation and possible benefit in the cancer population [Canakinumab Anti-Inflammatory Thrombosis Outcomes Study (CANTOS) and Colchicine Cardiovascular Outcomes Trial (COLCOT)]. Additionally, several other medications including PCSK9 inhibitors, sodium-glucose cotransporter-2 inhibitors (SGLT2i) and glucagon-like peptide 1 (GLP-1) agonists have been shown to modify inflammation, and therefore may provide cardiovascular benefits. While common pharmacotherapies used in CVD show promise in cancer survivors, their exact mechanisms remain poorly understood. Few studies evaluate their clinical effectiveness specifically in cancer survivors, as this patient population is excluded from most studies. Further investigation is warranted with more representation of cancer survivors before cost-effective recommendations are made. This is especially true in LMICs where resources are sparse for primary and secondary prevention in order to optimise care in this unique, high-risk population for CVD.

New Insights on the Toxicity on Heart and Vessels of Breast Cancer Therapies.

Cardiovascular diseases are largely represented in patients with cancer and appear to be important side effects of cancer treatments, heavily affecting quality of life and leading to premature morbidity and death among cancer survivors. In particular, treatments for breast cancer have been shown to potentially play serious detrimental effects on cardiovascular health. This review aims to explore the available literature on breast cancer therapy-induced side effects on heart and vessels, illustrating the molecular mechanisms of cardiotoxicity known so far. Moreover, principles of cardiovascular risk assessment and management of cardiotoxicity in clinical practice will also be elucidated. Chemotherapy (anthracycline, taxanes, cyclophosphamide and 5-fluorouracil), hormonal therapy (estrogen receptor modulator and gonadotropin or luteinizing releasing hormone agonists) and targeted therapy (epidermal growth factor receptor 2 and Cyclin-dependent kinases 4 and 6 inhibitors) adverse events include arterial and pulmonary hypertension, supraventricular and ventricular arrhythmias, systolic and diastolic cardiac dysfunction and coronary artery diseases due to different and still not well-dissected molecular pathways. Therefore, cardiovascular prevention programs and treatment of cardiotoxicity appear to be crucial to improve morbidity and mortality of cancer survivors.

Upregulation of Endothelin-1 May Predict Chemotherapy-Induced Cardiotoxicity in Women with Breast Cancer.

As survival in breast cancer patients from newer therapies increases, concerns for chemotherapy-induced cardiotoxicity (CIC) have offset some of these benefits, manifesting as a decline in left ventricular ejection fraction (LVEF). Patients receiving anthracycline-based chemotherapy followed by trastuzumab are at risk for CIC. Previous research evaluating whether clinical biomarkers predict cardiotoxicity has been inconsistent. Recently, angiotensin II type 1 receptor (ATR1) and endothelin 1 (ET1) have been shown to play a role in breast tumor growth. We evaluated ATR1 and ET1 expression in breast cancer tissue and its association with CIC. A total of 33 paraffin-embedded breast tissue specimens from women with breast cancer treated with anthracycline-based chemotherapy and trastuzumab were analyzed by immunohistochemistry (IHC) and qRT-PCR. We found that ET1 expression was increased in patients with an LVEF ≤ 50% (p = 0.032) with a lower LVEF correlating with higher ET1 expression (r = 0.377, p = 0.031). In patients with a change in LVEF of greater than 10%, greater ET1 expression was noted compared to those without a change in LVEF (p = 0.017). Increased ET1 expression in breast tumor tissue is associated with reduced LVEF. Future studies need to examine whether ET1 may be a tissue biomarker that helps predict the risk of developing CIC in women with breast cancer.

Solid Lipid Nanoformulation of Berberine Attenuates Doxorubicin Triggered in vitro Inflammation in H9c2 Rat Cardiomyocytes.

AIM: The aim of this study was to evaluate the efficacy of solid lipid nanoparticles of berberine against doxorubicin-induced cardiotoxicity. BACKGROUND: Berberine (Ber) is cardioprotective, but its oral bioavailability is low, and its effect on chemotherapy-induced cardiotoxicity has not been studied. OBJECTIVE: Solid lipid nanoparticles (SLNs) of berberine chloride were prepared, characterized and evaluated in vitro against doxorubicin-induced cardiomyocyte injury. METHODS: Berberine-loaded SLNs (Ber-SLNs) were synthesized using the water-in-oil microemulsion technique with tripalmitin, Tween 80 and poloxamer 407. Ber-SLNs were evaluated for preventive effect against toxicity of doxorubicin in H9c2 cells. The culture was pre-treated (24 h) with Ber (10 µM) and Ber-SLNs (1 and 10 µM), and 1 µM of doxorubicin (Dox) was added for 3 h. The cell viability assay (MTT (3-(4,5-Dimethylthiazol-2-yl-2,5-diphenyltetrazolium bromide) and LDH (Lactate dehydrogenase)), levels of Creatine kinase-MB (CK-MB), Nitrite, MDA (Malondialdehyde), ROS (Reactive oxygen species) generation, and apoptotic DNA (Deoxyribonucleic acid) content were assessed. RESULTS: Ber-SLNs had a mean particle size of 13.12±1.188 nm, the zeta potential of -1.05 ± 0.08 mV, poly-dispersity index (PDI) of 0.317 ± 0.05 and entrapment efficiency of 50 ± 4.8%. Cell viability was 81 ± 0.17% for Ber-SLNs (10 µM) and 73.22 ± 0.83% for Ber (10 µM) treated cells in the MTT assay. Percentage cytotoxicity calculated from LDH release was 58.91 ± 0.54% after Dox, 40.3 ± 1.3% with Ber (10 µM) and 40.7 ± 1.3% with Ber-SLNs (1 µM) (p<0.001). Inflammation and oxidative stress markers were lower with Ber and Ber-SLNs. Attenuation of ROS generation and apoptosis of cardiomyocytes were noted on fluorescence microscopy. CONCLUSION: Ber SLNs effectively prevented doxorubicin-induced inflammation and oxidative stress in rat cardiomyocytes. The results demonstrate that microemulsion is a simple and costeffective technique to prepare Ber-SLNs, and may be considered as a drug delivery vehicle for berberine.

CIRBP-OGFR axis safeguards against cardiomyocyte apoptosis and cardiotoxicity induced by chemotherapy.

Cold-inducible RNA-binding protein (CIRBP) is documented to be required for maintaining cardiac function, however, its role in chemotherapy-induced cardiotoxicity remains obscured. Herein, we report that CIRBP decreases cardiomyocyte apoptosis and attenuates cardiotoxicity through disrupting OGF-OGFR signal. CIRBP deficiency is involved in diverse chemotherapeutic agents induced cardiomyocyte apoptosis. Delivery of exogenous CIRBP to the mouse myocardium significantly mitigated doxorubicin-induced cardiac apoptosis and dysfunction. Specifically, OGFR was identified as a downstream core effector responsible for chemotherapy-induced cardiomyocyte apoptosis. CIRBP was shown to interact with OGFR mRNA and to repress OGFR expression by reducing mRNA stability. CIRBP-mediated cytoprotection against doxorubicin-induced cardiac apoptosis was demonstrated to largely involve OGFR repression by CIRBP. NTX as a potent antagonist of OGFR successfully rescued CIRBP ablation-rendered susceptibility to cardiac dyshomeostasis upon exposure to doxorubicin, whereas another antagonist ALV acting only on opioid receptors did not. Taken together, our results demonstrate that CIRBP confers myocardium resistance to chemotherapy-induced cardiac apoptosis and dysfunction by dampening OGF/OGFR axis, shedding new light on the mechanisms of chemo-induced cardiotoxicity and providing insights into the development of an efficacious cardioprotective strategy for cancer patients.

Resveratrol significantly improves cell survival in comparison to dexrazoxane and carvedilol in a h9c2 model of doxorubicin induced cardiotoxicity.

Cancer is one of the leading causes of deaths worldwide with 18.1 million deaths per year. Although there have been significant advances in anti-cancer therapies, they can often result in side effects with cardiovascular complications being the most severe. Dexrazoxane is the only currently approved treatment for prevention of anthracycline induced cardiotoxicity but there are concerns about its use due to the development of secondary malignancies and myelodysplastic syndrome. Additionally, it is only recommended in patients who are due to receive a total cumulative dose of 300 mg/m2 of doxorubicin or 540 mg/m2 of epirubicin. Thus, there exists an urgent need to develop new therapeutic strategies to counteract anthracycline induced cardiotoxicity. The h9c2 cardiomyoblast was investigated for its differentiation capacity and used to screen and compare promising prophylactics for doxorubicin induced cardiotoxicity. The half maximal inhibitory concentration of doxorubicin was determined in differentiated h9c2 cells after 24 h of exposure, to establish a model for drug screening. Cells were treated with dexrazoxane, resveratrol, and carvedilol either 3 h or 24 h prior to doxorubicin treatment. The ability of these cardioprotectants to prevent cardiotoxicity was analysed using the cck-8 cell viability assay and the dichlorofluorescin diacetate (DCFDA) reactive oxygen species (ROS) assay. There was no significant increase in survival in treatment groups after 3 h, however, at 24 h, resveratrol significantly improved survival compared to all other groups (p < 0.05). Additionally, dexrazoxane and resveratrol significantly decreased ROS formation at 3 h (p < 0.05) and all groups significantly decreased ROS production at 24 h (p < 0.001). This work is the first comparison of these cardioprotectants and suggests that resveratrol may be a more effective treatment in the prevention of anthracycline induced cardiotoxicity, compared to dexrazoxane and carvedilol. However, further work will be needed in order to decipher the exact mechanism and potential of this drug in the clinic.

Valor del strain longitudinal global en la detección precoz de cardiotoxicidad inducida por quimioterapia / Global longitudinal strain value in the early detection of chemotherapy-induced cardiotoxicity

RESUMEN Introducción: Los avances en la detección precoz y el tratamiento del cáncer han reducido de manera significativa la mortalidad. El resultado neto es el surgimiento de una cohorte de pacientes cuya supervivencia es suficiente para evidenciar los efectos secundarios de las terapias utilizadas. La cardiotoxicidad es el conjunto de enfermedades cardiovasculares derivadas de los tratamientos onco-hematológicos. Objetivos: Evaluar el papel de la deformación miocárdica (strain) longitudinal global en la detección precoz de cardiotoxicidad en pacientes con tratamiento quimioterápico. Método: Se realizó un estudio cuantitativo, analítico, longitudinal, prospectivo en 44 pacientes con diagnóstico de cáncer de mama o linfoma, que iniciaron tratamiento con quimioterapia en el Instituto de Oncología y Radiobiología de Cuba, en el período comprendido entre febrero de 2017 y abril de 2018. Se utilizaron métodos primarios y secundarios para la recolección del dato primario y se emplearon varias pruebas estadísticas para su análisis. Resultados: Las medias de edad y tiempo de tratamiento fueron de 47,7 años y 5,05 meses, respectivamente. Predominó la hipertensión arterial (18,1%) como factor de riesgo y la mayor cardiotoxicidad (27,8%) en pacientes con disfunción diastólica previa. Entre los que desarrollaron cardiotoxicidad, la variable que demostró mayor afectación fue el strain longitudinal global (p<0,0001), con una reducción de 19,6% respecto al basal. Conclusiones: El strain longitudinal global es un índice ecocardiográfico de deformación miocárdica, que presentó un valor discriminante significativo con respecto a la cardiotoxicidad en pacientes que recibieron tratamiento quimioterápico.

ABSTRACT Introduction: Advances in early detection and treatment of cancer have significantly reduced mortality. The net result is the emergence of a cohort of patients whose survival is sufficient to evidence the side effects of the used therapies. Cardiotoxicity is the set of cardiovascular diseases resulting from onco-hematological treatments. Objectives: To evaluate the role of global longitudinal strain in the early detection of cardiotoxicity in patients undergoing chemotherapy. Method: A quantitative, analytical, prospective, longitudinal study was carried out in 44 patients diagnosed with breast cancer or lymphoma, who started chemotherapy treatment at the Instituto de Oncología y Radiobiología of Cuba, from February 2017 to April 2018. Primary and secondary methods were used for raw data collection and several statistical tests were used for its analysis. Results: The mean age and treatment period were 47.7 years old and 5.05 months, respectively. The most prevalent risk factor was high blood pressure and cardiotoxicity was higher (27.8%) in patients with previous diastolic dysfunction. Among those who developed cardiotoxicity, the variable that showed the greatest affectation was global longitudinal strain (p<0.0001), with a reduction of 19.6% with respect to the basal one. Conclusions: Global longitudinal strain is an echocardiographic index of myocardial performance, which presented a significant discriminating value with respect to cardiotoxicity in patients who received chemotherapeutic treatment.

Utilidad de las técnicas de deformación miocárdica (strain) para evaluar cardiotoxicidad en pacientes con enfermedades oncológicas y tratamiento quimioterápico / Usefulness of myocardial strain techniques to assess cardiotoxicity in patients with oncologic diseases undergoing chemotherapy

RESUMEN Introducción: La evaluación de la función miocárdica es fundamental para la toma de decisiones durante el seguimiento de pacientes con enfermedades oncológicas que reciben quimioterapia. Con las técnicas de speckle-tracking bidimensional se puede determinar el grado de deformación de la fibra miocárdica y obtener una medida más directa de la función sistólica que la que aporta la fracción de eyección del ventrículo izquierdo (FEVI). Objetivo: Evaluar la función miocárdica, mediante ecocardiografía, en pacientes con enfermedades oncológicas y tratamiento quimioterápico. Método: Se realizó un estudio descriptivo longitudinal prospectivo en 21 pacientes con diagnóstico de enfermedad oncoproliferativa e indicación de quimioterapia con trastuzumab, en el Hospital de Fuerteventura (España), entre enero de 2017 y mayo de 2020. A todos se les realizó ecocardiograma transtorácico con técnica de speckle-tracking (strain longitudinal global) antes del tratamiento y durante el seguimiento. Resultados: Predominaron las mujeres (95,2%) con diagnóstico de cáncer de mama (90,5%) y la edad promedio fue de 53,8 años (rango 38-75). La FEVI y el strain longitudinal global fueron normales (100%) antes del inicio de la quimioterapia. Fue necesario suspender el tratamiento en 3 pacientes (14,3%); pero solo en 2 de ellos (9,5%) por cardiotoxicidad detectada por ecocardiografía. Cinco pacientes (23,8%) presentaron síntomas de insuficiencia cardíaca, 1 (4,8%) tenía cardiotoxicidad y en los otros 4 (19,0%) se demostró ausencia de disfunción miocárdica, por lo que se pudo continuar el tratamiento con seguridad. Conclusiones: El ecocardiograma con técnica de speckle-tracking bidimensional fue de vital importancia para evaluar la función miocárdica y guiar el tratamiento quimioterápico en pacientes con enfermedades oncológicas.

ABSTRACT Introduction: Assessment of myocardial function is critical for decision making during the follow-up of patients with oncologic diseases undergoing chemotherapy. Two-dimensional speckle-tracking techniques help to determine the degree of myocardial fiber deformation and provide a more direct measure of systolic function than left ventricular ejection fraction (LVEF). Objective: To evaluate myocardial function by means of echocardiography in patients with oncological diseases undergoing chemotherapy. Methods: A prospective longitudinal descriptive study was performed in 21 patients diagnosed with cancer and with indication for chemotherapy with trastuzumab, in the Hospital of Fuerteventura (Spain), between January 2017 and May 2020. All underwent transthoracic echocardiography with speckle-tracking technique (global longitudinal strain) before treatment and during follow-up. Results: Women (95.2%) with a diagnosis of breast cancer (90.5%) predominated and the mean age was 53.8 years (range 38-75). Left ventricular ejection fraction and global longitudinal strain were normal (100%) before starting chemotherapy. It was necessary to suspend treatment in 3 patients (14.3%); but only in 2 of them (9.5%) due to cardiotoxicity detected by echocardiography. Five patients (23.8%) presented symptoms of heart failure, 1 (4.8%) had cardiotoxicity and in the other 4 (19.0%) the absence of myocardial dysfunction was demonstrated, so that treatment could be continued safely. Conclusions: Two-dimensional speckle-tracking echocardiography was of vital importance for assessing myocardial performance and guiding chemotherapy in patients with oncologic diseases.

Antioxidant Approach as a Cardioprotective Strategy in Chemotherapy-Induced Cardiotoxicity.

Significance: Chemotherapy-induced cardiotoxicity (CTX) has been associated with redox signaling imbalance. In fact, redox reactions are crucial for normal heart physiology, whereas excessive oxidative stress can cause cardiomyocyte structural damage. Recent Advances: An antioxidant approach as a cardioprotective strategy in this setting has shown encouraging results in preventing anticancer drug-induced CTX. Critical Issues: In fact, traditional heart failure drugs as well as many other compounds and nonpharmacological strategies, with a partial effect in reducing oxidative stress, have been shown to counterbalance chemotherapy-induced CTX in this setting to some extent. Future Directions: Given the various pathways of toxicity involved in different chemotherapeutic schemes, interactions with redox balance need to be fine-tuned and a personalized cardioprotective approach seems to be required.

Strategies to Prevent Cardiotoxicity.

OPINION STATEMENT: Cardiovascular disease is a leading cause of death among cancer survivors. While the field of cardiology as a whole is driven by evidence generated through robust clinical trials, data in cardio-oncology is limited to a relatively small number of prospective clinical trials with heterogeneous groups of cancer patients. In addition, many pharmaceutical trials in oncology are flawed from a cardiovascular perspective because they exclude patients with significant cardiovascular (CV) history and have wide variation in the definitions of CV events and cardiotoxicity. Ultimately, oncology trials often underrepresent the possibility of cardiovascular events in a "real world" population. Thus, the signal for CV toxicity from a cancer treatment is often not manifested until phase IV studies; where we are often caught trying to mitigate the CV effects rather than preventing them. Most of the data about cardiotoxicity from cancer therapy and cardioprotective strategies has been developed from our experience in using anthracyclines for over 50 years with dramatic improvement in cancer survivorship. However, as we are in an era where cancer drug discovery is moving at lightning pace with increasing survival rates, it is imperative to move beyond anthracyclines and commit to research on the cardiovascular side effects of all aspects of cancer therapy with a focus on prevention. We emphasize the role of pre-cancer treatment CV assessment to anticipate cardiac issues and ultimately optimizing CV risk prior to cancer therapy as an opportunity to mitigate cardiovascular risk from cancer therapy.

Prevention of doxorubicin-induced Cardiotoxicity by pharmacological non-hypoxic myocardial preconditioning based on Docosahexaenoic Acid (DHA) and carvedilol direct antioxidant effects: study protocol for a pilot, randomized, double-blind, controlled trial (CarDHA trial).

BACKGROUND: Anthracycline-induced cardiotoxicity (AIC), a condition associated with multiple mechanisms of damage, including oxidative stress, has been associated with poor clinical outcomes. Carvedilol, a ß-blocker with unique antioxidant properties, emerged as a strategy to prevent AIC, but recent trials question its effectiveness. Some evidence suggests that the antioxidant, not the ß-blocker effect, could prevent related cardiotoxicity. However, carvedilol's antioxidant effects are probably not enough to prevent cardiotoxicity manifestations in certain cases. We hypothesize that breast cancer patients taking carvedilol as well as a non-hypoxic myocardial preconditioning based on docosahexaenoic acid (DHA), an enhancer of cardiac endogenous antioxidant capacity, will develop less subclinical cardiotoxicity manifestations than patients randomized to double placebo. METHODS/DESIGN: We designed a pilot, randomized controlled, two-arm clinical trial with 32 patients to evaluate the effects of non-hypoxic cardiac preconditioning (DHA) plus carvedilol on subclinical cardiotoxicity in breast cancer patients undergoing anthracycline treatment. The trial includes four co-primary endpoints: changes in left ventricular ejection fraction (LVEF) determined by cardiac magnetic resonance (CMR); changes in global longitudinal strain (GLS) determined by two-dimensional echocardiography (ECHO); elevation in serum biomarkers (hs-cTnT and NT-ProBNP); and one electrocardiographic variable (QTc interval). Secondary endpoints include other imaging, biomarkers and the occurrence of major adverse cardiac events during follow-up. The enrollment and follow-up for clinical outcomes is ongoing. DISCUSSION: We expect a group of anthracycline-treated breast cancer patients exposed to carvedilol and non-hypoxic myocardial preconditioning with DHA to show less subclinical cardiotoxicity manifestations than a comparable group exposed to placebo. TRIAL REGISTRATION: ISRCTN registry, ID: ISRCTN69560410. Registered on 8 June 2016.

Chemotherapy-Induced Cardiotoxicity in Adolescent After Heart Transplant: Do Not Forget the Right Ventricle.

The evaluation of oncologic patients at risk of chemotherapy-induced cardiotoxicity usually focuses on left ventricular function. However, recent studies have demonstrated that right ventricle impairment often coexists (and in some cases precedes) left-side affectation. We present the case of a 19-year-old heart transplant recipient who developed severe right ventricular dysfunction secondary to treatment of an abdominal lymphoma.

Pharmacogenetics of Chemotherapy-Induced Cardiotoxicity.

PURPOSE OF REVIEW: The goal of this review is to summarize current understanding of pharmacogenetics and pharmacogenomics in chemotherapy-induced cardiotoxicity. RECENT FINDINGS: Most of the studies rely on in vitro cytotoxic assays. There have been several smaller scale candidate gene approaches and a handful of genome-wide studies linking genetic variation to susceptibility to chemotherapy-induced cardiotoxicity. Currently, pharmacogenomic testing of all childhood cancer patients with an indication for doxorubicin or daunorubicin therapy for RARG rs2229774, SLC28A3 rs7853758, and UGT1A6*4 rs17863783 variants is recommended. There is no recommendation regarding testing in adults. There is clear evidence pointing to the role of pharmacogenetics and pharmacogenomics in cardiotoxicity susceptibility to chemotherapeutic agents. Larger scale studies are needed to further identify susceptibility markers and to develop pharmacogenomics-based risk profiling to improve quality of life and life expectancy in cancer survivors.

Modelling Chemotherapy-induced Cardiotoxicity by Human Pluripotent Stem Cells.

Novel antineoplastic therapies have greatly improved cancer survival; nevertheless they are bringing in new forms of cardiomyopathy, that can often limit proper cancer treatments. Novel cardioprotective therapies are therefore needed, for improving clinical outcomes in cancer patients. In order to test novel therapeutic strategies, there is an increasing need for appropriate experimental models of chemotherapy-induced cardiomyopathy. Induced pluripotent stem (iPS) cell- and human embryonic stem cell (hESC )-derived cardiomyocytes may be used as alternative in vitro models for studying mechanisms that underly chemotherapy-induced cardiomyopathy. In this review we discuss the use of iPS- and hESC-derived cardiomyocytes for evaluating additional pharmacological targets and for predicting chemotherapy-induced cardiotoxicity.