Cancer Therapeutics-related Cardiac Dysfunction Research Articles

Challenges in Implementing Optimal Echocardiographic Screening in Cardio-Oncology.

Echocardiography is the foundation of noninvasive screening in patients exposed to potentially cardiotoxic chemotherapeutic agents. Guidelines are becoming more consistent in regard to screening and recommend an integrative approach between cardiology and oncology providers as well as optimal non-invasive imaging modalities. Optimal screening with the latest technology will place a significant cost and administrative burden on echocardiographic laboratories and cardiology clinics. This review seeks to explore the latest studies regarding quality, cost, patient burden, and value related to implementing wide-spread screening for patients exposed to cardiotoxic chemotherapy. 3D and speckle tracking echocardiography are more reliable and can detect more subtle changes than traditional 2D volumes. Limited studies have revealed an uptake of optimal screening between 30 and 40%. Even fewer studies have evaluated the system-wide cost and value impact of screening in cardio-oncology or have evaluated patient-centered outcomes, such as cost and time burden. Finally, novel approaches, such as the use of point of care ultrasound with artificial intelligence guidance, may help alleviate these challenges. Screening patients at risk for cancer therapeutics-related cardiac dysfunction poses real-world challenges to our healthcare system. While modern echocardiographic techniques improve our ability to detect cardiac dysfunction, further research is needed to understand the challenges of wide-spread implementation.

Cardiac Troponins are Among Targets of Doxorubicin-Induced Cardiotoxicity in hiPCS-CMs.

Modern diagnostic strategies for early recognition of cancer therapeutics-related cardiac dysfunction involve cardiac troponins measurement. Still, the role of other markers of cardiotoxicity is still unclear. The present study was designed to investigate dynamics of response of human cardiomyocytes derived from induced pluripotent stem cells (hiPCS-CMs) to doxorubicin with the special emphasis on their morphological changes in relation to expression and organization of troponins. The hiPCS-CMs were treated with doxorubicin concentrations (1 and 0.3 µM) for 48 h and followed for next up to 6 days. Exposure of hiPCS-CMs to 1 µM doxorubicininduced suppression of both cardiac troponin T (cTnT) and cardiac troponin I (cTnI) gene expression. Conversely, lower 0.3 µM doxorubicin concentration produced no significant changes in the expression of aforementioned genes. However, the intracellular topography, arrangement, and abundance of cardiac troponin proteins markedly changed after both doxorubicin concentrations. In particular, at 48 h of treatment, both cTnT and cTnI bundles started to reorganize, with some of them forming compacted shapes extending outwards and protruding outside the cells. At later intervals (72 h and onwards), the whole troponin network collapsed and became highly disorganized following, to some degree, overall changes in the cellular shape. Moreover, membrane permeability of cardiomyocytes was increased, and intracellular mitochondrial network rearranged and hypofunctional. Together, our results demonstrate complex effects of clinically relevant doxorubicin concentrations on hiPCS-CM cells including changes in cTnT and cTnI, but also in other cellular compartments contributing to the overall cytotoxicity of this class of cytostatics.

Cardio-toxicity among patients with sarcoma: A Cardio-Oncology Registry.

e22530 Background: Chemotherapy induced cardio-toxicity has been recognized as a serious side effect since the first introduction to anthracycline (ANT). Cardio-toxicity among patients with breast cancer is well studied but the impact on patients with sarcoma is limited, even though they are exposed to higher ANT doses. The commonly used term for cardio-toxicity is cancer therapeutic related cardiac dysfunction (CTRCD), defined as a left ventricular ejection fraction (EF) reduction of > 10%, to a value below 53%. Our objective was to estimate the prevalence of CTRCD among patients with sarcoma, to evaluate echocardiography parameters associated with its development and whether CTRCD is associated with mortality. Methods: Data were collected as part of the International Cardio-Oncology Registry (ICOR), enrolling all patients who were evaluated in the cardio-oncology clinic at our institution. All sarcoma patients were enrolled and divided into two groups - CTRCD group vs. "Preserved EF" group. Results: Among 43 consecutive patients, 6 (14%) developed CTRCD. Elevated left ventricular end systolic diameter (p = 0.007) and a trend of reduced Global Longitudinal Strain (p = 0.092) were observed among the CTRCD group. During follow-up, 2 (33%) patients died in the CTRCD group vs. 3 (8.1%) patients in the "Preserved EF" group. In a multivariate analysis, adjusted to age and EF, CTRCD remained a significant predictor for mortality (p = 0.039). Conclusions: CTRCD is an important concern among patients with sarcoma, regardless of baseline risk factors, and is associated with mortality. Echocardiography parameters may provide an early diagnosis of cardio-toxicity.

Role of Speckle Tracking Echocardiography in the Evaluation of Breast Cancer Patients Undergoing Chemotherapy: Review and Meta-analysis of the Literature.

Diagnosis and management of Cancer therapeutics-related cardiac dysfunction is of crucial importance in breast cancer (BC) patients. The role of advanced echocardiographic techniques, such as deformation imaging, in the diagnosis and characterization of patients receiving cancer therapy has so far involved relatively small studies in the research setting. Therefore, we conducted a meta-analysis and systematic review of observational studies evaluating myocardial changes during chemotherapy detected through conventional echocardiographic parameters, such as 2D left ventricular ejection fraction (2D LVEF), and 2D Speckle tracking echocardiography (STE). The literature search retrieved 487 research works, articles, of which 17 were found to be pertinent with this topic. After full article review, 16 studies were considered suitable for the present analysis. Two separate analyses, one for the anthracyclines-based therapeutic regimen and one for the trastuzumab based therapeutic regimen, were performed. A significant reduction in 2D LVEF and 2D STE parameters during cancer therapy was found in both the investigations. Peak systolic global longitudinal strain demonstrated to be the most consistent 2D STE parameter in detecting early myocardial changes among all the studies. Thus, we confirmed the role of 2D STE for the early detection of myocardial damage, suggesting its crucial role in monitoring BC patients and eventually driving the introduction of cardioprotective treatment.

Cardiac Toxicity and Anthracyclines: Mechanism, Interventions, and the Trouble With Troponin.

As cancer survivorship increases, clinicians need to become educated regarding the long-term effect of cancer treatments. Cancer therapeutics–related cardiac dysfunction (CTRCD) is one such sequela that contributes to significant morbidity and mortality. Unfortunately, screening and management practices regarding CTRCD are inconsistent within guidelines and practice. This review will first look at anthracycline-related cardiac dysfunction occurrence and pathophysiology. Current guidelines for CTRCD screening will be discussed, including the use of 2D echocardiograms along with newer technology such as 3D echocardiography and global systolic longitudinal myocardial strain (GLS) measurements. Biomarkers like serum troponin demonstrate promise as an early indicator of cardiomyocyte injury and a potential means of risk stratification; however, guidelines vary regarding how best to incorporate elevated serum troponin levels into management plans. Growing evidence indicates the clinical need for early detection of CTRCD in order to initiate preventative pharmacologic management and improve patient outcomes.

Treatment of chemotherapy-associated cardiomyopathy.

The number of cancer survivors is increasing, and cardiovascular events are a significant cause of morbidity and mortality in these patients. Preexisting cardiovascular conditions as well as the development of cancer therapeutics-related cardiac dysfunction (CTRCD), in particular left ventricular dysfunction and heart failure, limit the options for cancer therapies for these patients and contribute to reduced cancer survival. Recent guidelines and position statements from various cardiology and oncology societies provide an outline for the practicing physician for the management of CTRCD. However, this is largely based on data extrapolated from the general heart failure population (including patients without cancers) and is not based on strong evidence. There is now emerging evidence for the prevention and treatment of heart failure related to certain established chemotherapeutic drugs, whereas there is lack of trials for specific cardioprotective strategies to reduce cardiotoxicity of newer targeted cancer therapies. In this article, we discuss the most recent literature for the management of asymptomatic left ventricular dysfunction and heart failure related to chemotherapy, from prevention to the use of goal-directed medical therapies as well as discuss the role for advanced heart failure treatment in this population.

Echocardiography and cancer therapeutics-related cardiac dysfunction.

Cancer therapeutics-related cardiac dysfunction (CTRCD) has become a leading cause of morbidity and mortality for cancer survivors, with the mortality rate for patients with CTRCD reportedly being as high as 60% by 2years after treatment. Although early detection of subclinical left ventricular (LV) dysfunction is essential for delaying progression to heart failure (HF) in patients with a history of using cardiotoxins, assessment of such dysfunction can be challenging. CTRCD may present initially as asymptomatic LV dysfunction and ultimately as symptomatic HF, which can occur even decades after discontinuation of the treatment. Once CTRCD has developed, the mortality rate is very high, because CTRCD is believed to be refractory to conventional pharmacological therapy and to be associated with a poor prognosis. Thus, there has been a growing interest in early detection of CTRCD by means of global longitudinal strain (GLS) assessed by two-dimensional speckle-tracking echocardiography, because it is a more sensitive and robust parameter for detecting subclinical LV dysfunction than other conventional LV functional parameters such as LV ejection fraction. This article reviews the utility of GLS for early detection of cardiotoxicity in patients during and after cancer chemotherapy, and future perspectives for the management of such patients.

Cardiac MRI: a Promising Diagnostic Tool to Detect Cancer Therapeutics–Related Cardiac Dysfunction

Recent advances in oncological research have led to a major improvement of mortality amongst cancer patients. However, survivors are at an increased risk to develop cancer therapeutics–related cardiac dysfunction (CTRCD). The management of CTRCD may pose a challenge due to its heterogeneous clinical presentation. This warrants the need for a multi-modality diagnostic tool to objectively acquire prognostic information for timely commencement of cardio-protective treatment. Cardiac magnetic resonance (CMR) imaging offers considerable potential due to its non-invasive, reproducible protocol. Moreover, biomarkers such as T1 and T2 mapping allow discrimination between oedematous and fibrotic myocardium, providing an invaluable diagnostic algorithm to track the temporal evolution of CTRCD. In this review, we appraise current evidence for the role of CMR in the management of CTRCD, placing emphasis on ventricular function, strain, late gadolinium enhancement and parametric mapping. We recommend a central role for CMR in the interdisciplinary management of CTRCD.

BASELINE ECHOCARDIOGRAPHIC PARAMETERS TO PREDICT CARDIOTOXICITY IN BREAST CANCER PATIENTS RECEIVING CHEMOTHERAPY

Breast cancer is often treated with anthracyclines and HER2 inhibitors, which are well-known cardiotoxic agents. Cancer therapeutics related cardiac dysfunction (CTRCD) has been defined by most guidelines using arbitrary left ventricular ejection fraction (LVEF) cut-off points or decreases. Our

Echocardiographic Assessment for the Detection of Cardiotoxicity Due to Vascular Endothelial Growth Factor Inhibitor Therapy in Metastatic Renal Cell and Colorectal Cancers

Cardio-oncology is a recently established discipline that focuses on the management of patients with cancer who are at risk for developing cardiovascular complications as a result of their underlying oncologic treatment. In metastatic colorectal cancer (mCRC) and metastatic renal cell carcinoma (mRCC), vascular endothelial growth factor inhibitor (VEGF-i) therapy is commonly used to improve overall survival. Although these novel anticancer drugs may lead to the development of cardiotoxicity, whether early detection of cardiac dysfunction using serial echocardiography could potentially prevent the development of heart failure in this patient population requires further study. The aim of this study was to investigate the role of two-dimensional speckle-tracking echocardiography in the detection of cardiotoxicity due to VEGF-i therapy in patients with mCRC or mRCC. Patients with mRCC or mCRC were evaluated using serial echocardiography at baseline and 1, 3, and 6months following VEGF-i treatment. A total of 40 patients (34 men; mean age, 63±9years) receiving VEGF-i therapy were prospectively recruited at two academic centers: 26 (65%) were receiving sunitinib, eight (20%) pazopanib, and six (15%) bevacizumab. The following observations were made: (1) 8% of patients developed clinically asymptomatic cancer therapeutics-related cardiac dysfunction; (2) 30% of patients developed clinically significant decreases in global longitudinal strain, a marker for early subclinical cardiac dysfunction; (3) baseline abnormalities in global longitudinal strain may identify a subset of patients at higher risk for developing cancer therapeutics-related cardiac dysfunction; and (4) new or worsening hypertension was the most common adverse cardiovascular event, afflicting nearly one third of the study population. Cardiac dysfunction defined by serial changes in myocardial strain assessed using two-dimensional speckle-tracking echocardiography occurs in patients undergoing treatment with VEGF-i for mCRC or mRCC, which may provide an opportunity for preventive interventions.

Baseline Global Longitudinal Strain as a Predictor of Left Ventricular Dysfunction and Hospitalization for Heart Failure of Patients With Malignant Lymphoma After Anthracycline Therapy.

Our aim was to investigate the baseline clinical and echocardiographic parameters for predicting left ventricular (LV) dysfunction after anthracycline chemotherapy and heart failure (HF) hospitalization in a single cancer disease. Methods and Results: We studied 73 patients with malignant lymphoma and preserved LV ejection fraction (LVEF). Echocardiography was performed before and after anthracycline chemotherapy. Global longitudinal strain (GLS) was determined from 3 standard apical views. LV dysfunction after anthracycline chemotherapy was defined according to the current definition of cancer therapeutics-related cardiac dysfunction. Long-term (50-month) unfavorable outcome was prespecified as hospitalization for HF. A total of 10 patients had LV dysfunction after anthracycline chemotherapy. Multivariate logistic regression analysis showed that baseline GLS was the only independent predictor of this dysfunction. Receiver-operating characteristic curve analysis identified the optimal GLS cutoff for predicting LV dysfunction after anthracycline chemotherapy as ≤19% (P=0.008). Furthermore, the Kaplan-Meier curve indicated that fewer patients with GLS >19% were hospitalized for HF than among those with GLS ≤19% (log-rank P=0.02). For sequential logistic models, a model based on baseline clinical variables (χ2=2.9) was improved by the addition of baseline LVEF (χ2=9.0; P=0.01), and further improved by the addition of baseline GLS (χ2=13.1, P=0.04). Watchful observation or early therapeutic intervention with established cardioprotective medications may be necessary for patients with malignant lymphoma and preserved LVEF but with abnormal GLS.

Usefulness of Global Longitudinal Strain for Early Identification of Subclinical Left Ventricular Dysfunction in Patients With Active Cancer

Cardiotoxicity from cancer therapy has become a leading cause of morbidity and mortality in cancer survivors. The most commonly used definition is cancer therapeutic related cardiac dysfunction defined as a left ventricular ejection fraction (LVEF) reduction of >10%, to a value below 50%. However, according to the recent American and European Society of Echocardiography, global longitudinal strain (GLS) is the optimal parameter for early detection of subclinical left ventricular dysfunction. The objective of this study was to evaluate the frequency of GLS reduction in patients with active cancer and its correlation to other echocardiographic parameters. Data were collected as part of the International Cardio-Oncology Registry. All patients performed at least 2 echocardiograms including GLS. We evaluated the frequency of GLS reduction (≥10% relative reduction), its correlation to LVEF reduction and whether there are other predicting echocardiographic parameters. In 64 consecutive patients, 12 (19%) had ≥10% GLS relative reduction, of which 75% had no concomitant ejection fraction reduction. There were no significant differences in the baseline cardiac risk factors (hypertension, diabetes, hyperlipidemia, or smoking). Treatment with Doxorubicin, Pertuzumab, or Ifosfamide was significantly more frequent in patients GLS reduction. No other echocardiographic parameters, including diastolic function or systolic pulmonary artery pressure were significant predictors for GLS reduction. In conclusion, our study demonstrates that GLS reduction is frequent in active cancer patients, precedes LVEF reduction and cannot be anticipated by other echocardiographic parameters. Using GLS routinely during therapy may lead to an early diagnosis of cardiotoxicity.

Usefulness of Left Atrial Remodeling in Predicting CardiacToxicity During Trastuzumab Therapy for Breast Cancer

Trastuzumab is a key therapy for patients with human epidermal growth factor receptor 2 positive breast cancer (BC). However, it may cause left ventricular dysfunction, resulting in withdrawal of therapy. Left atrium (LA) enlargement has proven to cue subclinical ventricular dysfunction in various clinical setting. Aim of the study was to investigate the association between LA volume index (LAVI) change over time and the development of Cancer Therapeutics Related Cardiac Dysfunction (CTRCD). Consecutive human epidermal growth factor receptor 2 positive BC patients were retrospectively included. Transthoracic echocardiography was performed before starting Trastuzumab and at every 3 up to 12 months. LA volume was measured using the modified Simpson's rule and indexed for body surface area. Ninety patients formed the study population. All patients had a complete 12 months follow-up. Mean baseline LAVI was 27 ± 8 ml/m2 and it was dilated (≥34 ml/m2) in 10 patients (11%). During follow-up, CTRCD occurred in 19 (21%) patients and there was modest LAVI enlargement, with a mean increase of 3 ± 2 ml/m2 (p = 0.0002vs. baseline). LAVI dilation was significantly higher in patients with CTRCD (average increase at the time of CTRCD vs. baseline: 7 ± 6 ml/m2, p = 0.008), versus patients without CTRCD (average increase at 12 months of follow-up 2±1, p = 0.02), p for comparison = 0.004. LAVI dilatation over time predicted CTRCD independently from baseline LAVI values and the presence of systemic arterial hypertension (OR for 5 ml/m2 dilation was 1.56 [95%CI 1.09 to 2.37], p = 0.01). Trastuzumab related CTRCD is associated with significant LAVI morphological remodeling in BC patients.

Evolution of echocardiography in subclinical detection of cancer therapy-related cardiac dysfunction.

Cancer therapies have resulted in increased survivorship in oncological patients. However, the benefits have been marred by the development of premature cardiovascular disease. The current definition outlines measurement of ejection fraction as a mean to diagnose cancer therapeutic-related cardiac dysfunction (CTRCD); however, up to 58% of the patients do not regain their cardiac function after the CTRCD diagnosis, despite therapeutic interventions. Therefore, there has been a growing interest in the markers for early myocardial changes (ie, changes with normal left ventricular ejection fraction [LVEF]) that may predict the development of subsequent left ventricular ejection fraction reduction or progression to heart failure. This review will highlight the use of diastolic parameters, tissue Doppler imaging (TDI), and speckle tracking echocardiogram (STE) as emerging technologies which can potentially detect cardiac dysfunction thereby stratifying patients for cardioprotective therapies. The goal of this manuscript was to highlight the concepts and discuss the current controversies surrounding these echocardiographic imaging modalities.

Usefulness of Integrating Heart Failure Risk Factors Into Impairment of Global Longitudinal Strain to Predict Anthracycline-Related Cardiac Dysfunction

The prediction of cancer therapeutics-related cardiac dysfunction (CTRCD) is an essential aspect of care for individuals who receive potentially cardiotoxic oncologic treatments. Certain clinical risk factors have been described for incident CTRCD, and measurement of left ventricular (LV) longitudinal strain by speckle tracking 2-dimensional echocardiography (2DE) is the best-validated myocardial mechanical imaging assessment to detect subtle changes in LV function during cancer treatment. However, the direct integration of clinical and imaging risk factors to predict CTRCD has not yet been extensively examined. This was a retrospective study of 183 women with breast cancer aged 50.9 ± 10.8 years who received treatment with anthracyclines (doxorubicin dose of 422 ± 69 mg/m2, with 41.2% of subjects also receiving trastuzumab) and underwent 2DE at clinically determined intervals. CTRCD was diagnosed when LV ejection fraction dropped ≥10% to a subnormal (<53%) value by 2DE. Left ventricular global longitudinal strain (LV-GLS) was assessed offline. The risk prediction tool based only on clinical factors previously described by Ezaz etal was applied to our cohort and accurately stratified these subjects into low-, intermediate-, and high-risk groups, with incident CTRCD in 7.4%, 26.9%, and 54.6%, respectively (chi-square = 20.7, p <0.0001). We developed novel multivariate models to predict CTRCD using (1) demographic variables only (c = 0.8674), (2) echocardiographic (peak LV-GLS) variables only (c = 0.8440), or (3) a combination of demographic and echocardiographic variables, with the combined model exhibiting superior receiver-operating characteristics (c = 0.9629). In conclusion, estimation of CTRCD risk should integrate all available data, including both clinical variables and an imaging assessment.

Cardiac Imaging: Multimodality Advances and Surveillance Strategies in Detection of Cardiotoxicity.

Contemporary cancer management has increased the overall number of cancer survivors, but cardiotoxicity remains a subject of concern, which is a major cause of noncancer mortality among survivors. Among the potential cardiovascular complications, left ventricular (LV) systolic dysfunction is a poor prognostic factor. The importance of its early detection is based on the principle that the likelihood of response to heart failure (HF) treatment is temporally related to the initiation of HF treatment. For these reasons, cardiac monitoring is commonly applied in general practice, based on serial measurements of LV ejection fraction (LVEF); transthoracic echocardiography (TTE) is generally used. However, the LVEF, as a diagnostic and predictive parameter, has significant limitations, which calls for more effective multimodality imaging strategies. This approach requires further study, but there is increasing available data in the literature, encouraging the combination of multimodality imaging parameters and techniques for early cancer therapeutic-related cardiac dysfunction (CTRCD) detection.

Arginine-Nitric Oxide Metabolites and Cardiac Dysfunction in Patients With Breast Cancer

BackgroundOxidative/nitrosative stress and endothelial dysfunction are hypothesized to be central to cancer therapeutics–related cardiac dysfunction (CTRCD). However, the relationship between circulating arginine-nitric oxide (NO) metabolites and CTRCD remains unstudied. ObjectivesThis study sought to examine the relationship between arginine-NO metabolites and CTRCD in a prospective cohort of 170 breast cancer patients treated with doxorubicin with or without trastuzumab. MethodsPlasma levels of arginine, citrulline, ornithine, asymmetric dimethylarginine (ADMA), symmetric dimethylarginine (SDMA), and N-monomethylarginine (MMA) were quantified at baseline, 1 month, and 2 months after doxorubicin initiation. Determinants of baseline biomarker levels were identified using multivariable linear regression, and Cox regression defined the association between baseline levels and 1- or 2-month biomarker changes and CTRCD rate in 139 participants with quantitated echocardiograms at all time points. ResultsAge, hypertension, body mass index, and African-American race were independently associated with ≥1 of baseline citrulline, ADMA, SDMA, and MMA levels. Decreases in arginine and citrulline and increases in ADMA were observed at 1 and 2 months (all p < 0.05). Overall, 32 participants experienced CTRCD over a maximum follow-up of 5.4 years. Hazard ratios for ADMA and MMA at 2 months were 3.33 (95% confidence interval [CI]: 1.12 to 9.96) and 2.70 (95% CI: 1.35 to 5.41), respectively, and 0.78 (95% CI: 0.64 to 0.97) for arginine at 1 month. ConclusionsIn breast cancer patients undergoing doxorubicin therapy, early alterations in arginine-NO metabolite levels occurred, and early biomarker changes were associated with a greater CTRCD rate. Our findings highlight the potential mechanistic and translational relevance of this pathway to CTRCD.

Developing a cardiac monitoring plan in at-risk cancer survivors.

133 Background: Improvements in early detection, screening, and treatment of cancer translate into survivors living longer, highlighting the need for guidelines to address the late and long-term effects of cancer treatment. A particularly concerning effect is Cancer Therapeutics-Related Cardiac Dysfunction (CTRCD). Cancer treatments can result in a range of cardiovascular toxicity including left ventricular dysfunction, heart failure and radiation-induced heart disease (RIHD). Various consensus statements related to cardiovascular care for adult cancer survivors exist; however there are no globally accepted follow-up guidelines. Our purpose is to create a protocol to stratify a survivor’s cardiac risk and provide a basis for follow-up recommendations. Methods: We first evaluated existing resources within our institution and identified key stakeholders who were recruited to form a multidisciplinary workgroup (2 survivorship advanced practice providers, an oncologist, a radiation oncologist, and 2 cardio-oncologists). We then reviewed current research and literature on cardiotoxic cancer therapies and identified two consensus statements from the American Society of Echocardiography and the European Association of Cardiovascular Imaging which helped inform our protocol. Finally, we created a cardiac assessment that could be applied in the pre-treatment phase and extend into the post-treatment phase. Results: Two assessment tools were developed. The first is an algorithm initiated in the pre-treatment setting by an oncologist when a Type I or Type II cardiotoxic agent is planned. The second is a risk assessment tool that is initiated in the post-treatment setting to stratify cardiac risk and provide follow-up recommendations. Conclusions: Development of standardized guidelines for assessment and treatment of late and long-term effects of treatment is critical. This protocol has been developed to account for the many factors that contribute to overall cardiac risk after various anti-cancer therapies. Further data is needed to evaluate long-term cardiac and survival outcomes based on this protocol.

Cardiac mechanics and dysfunction with anthracyclines in the community: results from the PREDICT study

BackgroundOur objective was to determine the relevance of changes in myocardial mechanics in diagnosing and predicting cancer therapeutics-related cardiac dysfunction (CTRCD) in a community-based population treated with anthracyclines.MethodsQuantitative measures of...

Baseline Immunoglobulin E Levels as a Marker of Doxorubicin- and Trastuzumab-Associated Cardiac Dysfunction.

There is a critical need to develop robust, mechanistic strategies to identify patients at increased risk of cancer therapeutics-related cardiac dysfunction (CTRCD). We aimed to discover new biomarkers associated with doxorubicin- and trastuzumab-induced CTRCD using high-throughput proteomic profiling. Plasma, echocardiograms, and clinical outcomes were collected at standardized intervals in breast cancer patients undergoing doxorubicin and trastuzumab cancer therapy. Thirty-one longitudinal plasma samples from 3 cases with CTRCD and 4 age- and cancer-matched controls without CTRCD were processed and analyzed using label-free liquid chromatography-mass spectrometry. From these analyses, 862 proteins were identified from case/control pairs 1 and 2 and 1360 proteins from case/control pair 3. Proteins with a >1.5-fold change in cases compared with controls with a P<0.05 either at the time of CTRCD diagnosis or across all time points were considered candidate diagnostic or predictive biomarkers, respectively. The protein that demonstrated the largest differences between cases and controls was immunoglobulin E, with higher levels detected at baseline and across all time points in controls without CTRCD as compared with matched CTRCD cases (P<0.05). Similarly, in a validation study of 35 participants treated with doxorubicin and trastuzumab, high baseline immunoglobulin E levels were associated with a significantly lower risk of CTRCD (P=0.018). In patients receiving doxorubicin and trastuzumab, high baseline immunoglobulin E levels are associated with a lower risk of CTRCD. These novel findings suggest a new paradigm in cardio-oncology, implicating the immune system as a potential mediator of doxorubicin- and trastuzumab-induced cardiac dysfunction.