Risk of anthracycline-induced cardiac dysfunction in adolescent and young adult (AYA) cancer survivors: role of genetic susceptibility loci.

There is a known genetic susceptibility to anthracycline-induced cardiac dysfunction in childhood cancer survivors, but this has not been adequately shown in adolescent and young adult (AYA) patients. Our aim was to determine if the previously identified variants associated with cardiac dysfunction in childhood cancer patients affect AYA cancer patients similarly. Forty-five variants were selected for analysis in 253 AYAs previously treated with anthracyclines. We identified four variants that were associated with cardiac dysfunction: SLC10A2:rs7319981 (p = 0.017), SLC22A17:rs4982753 (p = 0.019), HAS3:rs2232228 (p = 0.023), and RARG:rs2229774 (p = 0.050). HAS3:rs2232228 and SLC10A2:rs7319981 displayed significant effects in our AYA cancer survivor population that were in the opposite direction than that reported in childhood cancer survivors. Genetic variants in the host genes were further analyzed for additional associations with cardiotoxicity in AYA cancer survivors. The host genes were then evaluated in a panel of induced pluripotent stem cell-derived cardiomyocytes to assess changes in levels of expression when treated with doxorubicin. Significant upregulation of HAS3 and SLC22A17 expression was observed (p < 0.05), with non-significant anthracycline-responsivity observed for RARG. Our study demonstrates that there is a genetic influence on cardiac dysfunction in AYA cancer patients, but there may be a difference in the role of genetics between childhood and AYA cancer survivors.

Cardiovascular events in patients treated with chimeric antigen receptor T-cell therapy for aggressive B-cell lymphoma.

Standard of care (SOC) chimeric antigen receptor (CAR) T-cell therapies such as axicabtagene ciloleucel (axi-cel) and tisagenlecleucel (tisa-cel) are associated with multisystem toxicities. There is limited information available about cardiovascular (CV) events associated with SOC axi-cel or tisa-cel. Patients with CV comorbidities, organ dysfunction, or lower performance status were often excluded in the clinical trials leading to their Food and Drug Adminsitration approval. An improved understanding of CV toxicities in the real-world setting will better inform therapy selection and management of patients receiving these cellular therapies. Here, we retrospectively reviewed the characteristics and outcomes of adult patients with relapsed/refractory large B-cell lymphoma treated with SOC axi-cel or tisa-cel. Among the 165 patients evaluated, 27 (16%) developed at least one 30-day (30-d) major adverse CV event (MACE). Cumulatively, these patients experienced 21 arrhythmias, four exacerbations of heart failure/cardiomyopathy, four cerebrovascular accidents, three myocardial infarctions, and one patient died due to myocardial infaction. Factors significantly associated with an increased risk of 30-d MACE included age ≥60 years, an earlier start of cytokine release syndrome (CRS), CRS ≥ grade 3, long duration of CRS, and use of tocilizumab. After a median follow-up time of 16.2 months (range, 14.3-19.1), the occurrence of 30-d MACE was not significantly associated with progression-free survival or with overall survival. Our results suggest that the occurrence of 30-d MACE is more frequent among patients who are elderly, with early, severe, and prolonged CRS. However, with limited follow-up, larger prospective studies are needed, and multidisciplinary management of these patients is recommended.

Tricuspid annular plane systolic excursion is a predictor of mortality for septic shock.

BACKGROUND: Cardiac dysfunction is a common sequela in patients with sepsis and multi-organ dysfunction. Echocardiography is commonly used in the investigation of circulatory failure. AIMS: We aimed to evaluate the prognostic value of echocardiographic parameters in patients with septic shock. METHODS: This study was a retrospective trial. We included patients who were admitted to intensive care unit (ICU) with septic shock. The patients' echocardiograms, clinical data and outcomes were obtained from their medical records. Associations between echocardiogram variables and mortality were assessed using logistic regression, controlled for age, sex, body mass index and the interval between the ICU admission and echocardiogram. The utility of statistically significant echocardiogram variables to predict mortality were assessed using receiver operating characteristic (ROC) curves. RESULTS: The outcomes presented that tricuspid annular plane systolic excursion (TAPSE) was statistically significantly associated with both ICU (P = 0.02) and 90-day (P = 0.001) mortality. From the ROC curves, TAPSE emerged a significant and moderate predictor for 90-day (area under curve (AUC) = 0.69, 95% CI = 0.565-0.814) and in-ICU mortality (AUC = 0.762, 95% CI = 0.652-0.871). The optimal cut-off for TAPSE was 2.1 cm for both 90-day mortality (sensitivity of 80% and specificity and 58%) and in-ICU mortality (sensitivity of 69% and specificity of 77%). CONCLUSIONS: TAPSE was associated with increased mortality in those with sepsis and suspicion of cardiac dysfunction. This is a hypothesis generating article that an association may be present and requires significant more work with expansion to the entire population base.

Role of myocardial strain imaging in surveillance and management of cancer therapeutics-related cardiac dysfunction: A systematic review.

Transthoracic echocardiography is the primary cardiac imaging modality for the detection of Cancer Therapeutics-Related Cardiac Dysfunction (CTRCD) through evaluation of serial changes in left ventricular ejection fraction (LVEF). However, LVEF assessment by standard methods including 3D Echo has important limitations including the fact that reduction in LVEF occurs late in the process of CTRCD. In contrast, by detecting early myocardial change, myocardial strain or deformation imaging has evolved to be a preferred parameter for detecting CTRCD. Peak systolic global longitudinal strain (GLS) by speckle-tracking echocardiography (STE) has become an important prechemotherapy parameter that can independently predict subsequent adverse cardiac events as these abnormalities typically precede reduction in LVEF. While an absolute GLS measurement may be informative, a 10%-15% early reduction in GLS by STE appears to be the most useful prognosticator for cardiotoxicity while on therapy. In this paper, we present a current systematic literature review of application of myocardial strain imaging in cancer patients performed following PRISMA guidelines using electronic databases from MEDLINE, Embase, and SCOPUS Library from their inception until June 11th 2020. This review demonstrates the incremental value of myocardial deformation imaging over traditional LVEF in detection and its clinical implication in management of CTRCD.

Modern Radiotherapy and Risk of Cardiotoxicity.

Despite the advancements of modern radiotherapy, radiation-induced heart disease remains a common cause of morbidity and mortality amongst cancer survivors. This review outlines the basic mechanism, clinical presentation, risk stratification, early detection, possible mitigation, and treatment of this condition.

Cardiovascular manifestations of Erdheim-Chester disease.

INTRODUCTION: Erdheim-Chester disease is a rare, multisystem hematologic disease. Cardiovascular involvement is seen in patients with Erdheim-Chester disease and can lead to increased morbidity and mortality. In this series, we report various cardiovascular manifestations of patients with Erdheim-Chester disease. METHODS: This study includes patients with Erdheim-Chester disease who were referred to our institution from 12/3/2009 through 12/13/2017. All patients had biopsy-proven Erdheim-Chester disease. Clinical data, multimodality imaging, and cardiac tests were reviewed. RESULTS: Cardiovascular findings in 24 patients with Erdheim-Chester disease were included in the study. We reviewed available transthoracic echocardiograms, whole body PET/CT scans, and CMR studies. Most patients were male and mean age at the time of diagnosis was 58 years. Pericardial involvement (13%), myocardial infiltration (25%), endocardial involvement (4%), valvular disease (17%), aortic/vascular disease (17%), conduction system infiltration (8%), and coronary artery disease (25%) were present. At a median follow-up of 5.5 years, mortality was 17%. CONCLUSIONS: Erdheim-Chester disease can involve various cardiovascular structures and is frequently diagnosed on an imaging modality. Some patients had asymptomatic involvement, but others presented with ischemic heart disease, heart failure, valvular disease, and conduction system abnormalities. Early recognition of cardiovascular involvement of Erdheim-Chester disease is needed because of high morbidity and mortality.

Chemotherapeutic Agents and the Risk of Ischemia and Arterial Thrombosis.

PURPOSE OF REVIEW: Numerous chemotherapeutic agents have been associated with the development of ischemia and arterial thrombosis. As newer therapies have been developed to treat cancer, some of these chemotherapy drugs have been implicated in the development of vascular disease. In this review, we will summarize the most common chemotherapeutic drug classes that may play a role in the development of ischemic heart disease. RECENT FINDINGS: Angiogenesis inhibitors, alkylating agents, antimetabolites, antimicrotubules, and proteasome inhibitors have a number of cardiovascular toxicities. The possible mechanisms of action of these drugs leading to ischemic complications are varied but include endothelial dysfunction, platelet aggregation, reduced levels of nitrous oxide (NO), and elevated levels of reactive oxygen species (ROS), and vasospasm. While some drugs act through multiple pathways that result in the development of ischemic heart disease, others such as the antimetabolites and antimicrotubules appear to primarily cause vasospasm. Furthermore, while aromatase inhibitors increase the risk of heart disease in comparison to tamoxifen in large studies, this finding likely occurs because of a protective role of tamoxifen on cardiovascular risk factors rather than a direct effect of aromatase inhibitors. Angiogenesis inhibitors, alkylating agents, antimetabolites, antimicrotubules, and proteasome inhibitors can lead to ischemic complications in patients with cancer. Many of these drugs have proven to be effective in improving cancer prognosis, but their possible cardiovascular effects have to be carefully monitored and treated. Treatment of ischemic complications in the setting of cancer therapy should focus on the optimal medical management of known cardiovascular risk factors and follow an evidence-based approach.

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.

Echocardiographic measures associated with the presence of left ventricular thrombus in patients with chemotherapy-related cardiac dysfunction.

BACKGROUND: Previous studies have not evaluated the prevalence and specific risk factors for the development of left ventricular (LV) thrombus in patients with severely reduced left ventricular dysfunction due to chemotherapy-related cardiomyopathy. We sought to evaluate the prevalence and potential markers of LV thrombus in this patient population. METHODS: From January 2009 to December 2013, patients with chemotherapy-related severe LV dysfunction (LV ejection fraction [LVEF] ≤ 30%) identified from MD Anderson Cancer Center database were reviewed. Patient characteristics and echocardiographic parameters were analyzed to determine potential risk factors for LV thrombus. RESULTS: A total of 121 patients met inclusion criteria (age 54.8 ± 15.2 years; female 63.6%; LVEF 26.3 ± 4%). LV thrombus was present in 9 patients (7.4%). Patients with LV thrombus have significantly lower LVEF compared to those without (18.7 ± 3.8% vs 26.9 ± 3.4%, P < .0001). Prevalence of LV thrombus increased as LVEF decreased and was the highest in patients with LVEF < 20%. By univariate analysis, decreased LVEF, particularly LVEF < 20% (OR 36.30, 95% CI 7.35-179.25, P < .0001) and restrictive LV filling pattern (OR 18.13, 95% CI 4.17-78.89, P = .0001) were associated with presence of LV thrombus. CONCLUSION: In patients with severely reduced LV systolic function due to chemotherapy-induced cardiomyopathy, LV thrombus was found in 7.4% of subjects. Severely decreased LVEF (<20%) and restrictive LV filling pattern were associated with the presence of LV thrombus.

Predictors of left ventricular systolic function recovery in the setting of sinus tachycardia in patients with cancer.

OBJECTIVES: To identify unique echocardiographic features that could be used to reliably predict LVEF recovery upon resolution of sinus tachycardia in patients with cancer. BACKGROUND: Sinus tachycardia may be a manifestation of underlying cardiomyopathy or can lead to a reversible form of dilated cardiomyopathy known as tachycardia-mediated cardiomyopathy. While distinguishing the two can be challenging, predicting recovery regardless of cause can be of significant clinical importance in the cancer population. METHODS: Results of echocardiograms performed were collected. Patients with a repeat echocardiogram within 6 months of the initial echocardiogram were included. Patients with structural heart disease, acute coronary syndrome, sepsis, and pericardial disease were excluded. A comparison between baseline echocardiogram and subsequent echocardiogram was made to determine whether specific echocardiographic parameters predicted LVEF recovery. Two groups of patients were defined at the outset of the study. The recovered group was comprised of patients with reduced LVEF in the setting of sinus tachycardia and normal LVEF with resolution of tachycardia to normal sinus rhythm (NSR). The unrecovered group was comprised of subjects with low LVEF in the setting of both sinus tachycardia and NSR. RESULTS: A total of 40 patients were included in the study. LVEF in the recovered group (n=18) was 42.8% with sinus tachycardia and increased to 58.3% with NSR. Average LVEF in the unrecovered group (n=22) was 35.1% with tachycardia and improved to 38.5% with NSR. Medial TDI (E') was significantly greater in the recovered group with both tachycardia (7.95 cm/s versus 4.56 cm/s, P<.001) and NSR (8.11 cm/s versus 5.13 cm/s, P<.001). Similarly, lateral TDI (E') was significantly greater in the recovered group than in the unrecovered group during tachycardia (8.97 cm/s versus 5.13 cm/s, P<.001) and NSR (9.05 cm/s versus 5.13 cm/s, P<.001). Multivariable logistic regression analysis showed that medial TDI >6.5 cm/s (OR=30.9, P=.001) and lateral TDI >7.8 cm/s (OR=52.5, P=.002) are positively associated with the probability of LVEF recovery. CONCLUSIONS: In conclusion, TDI (medial E'>6.5 cm/s; lateral E'>7.8 cm/s) appears to predict LVEF recovery in patients with sinus tachycardia upon resolution of the tachycardia in patients with cancer.

Does Thrombolysis Have a Place in the Cardiopulmonary Resuscitation of Patients With Acute Pulmonary Embolism? A Case of Successful Thrombolysis During Pulmonary Embolism Induced Cardiopulmonary Arrest.

OBJECTIVE: Pulmonary embolism often causes cardiac arrest. When this occurs, thrombolytic therapy is not routinely administered. There are multiple reasons for this, including difficulty with rapidly adequately diagnosing the embolus, the lack of good data supporting the use of thrombolytics during resuscitation, the belief that thrombolytic therapy is ineffective once a patient has already arrested, the difficulty of obtaining thrombolytics at the bedside rapidly enough to administer during a code, and the increased risks of bleeding, particularly with ongoing chest compressions. In this case report, we present a patient who was successfully treated with thrombolytic therapy during pulmonary embolism-induced cardiopulmonary arrest and discuss the role of thrombolytics in cardiopulmonary resuscitation. DESIGN: Case report. SETTING: Surgical ICU in a comprehensive cancer center. PATIENT: A 56-year-old man who developed hypotension, dyspnea, hypoxia, and pulseless electrical activity 10 days after resection of a benign colon lesion with a right hemicolectomy and primary end-to-end anastomosis. INTERVENTIONS: After a rapid bedside echocardiogram suggesting pulmonary embolus, thrombolytic therapy was administered during cardiopulmonary resuscitative efforts. MEASUREMENTS AND MAIN RESULTS: The patient had a return of spontaneous circulation and showed improvement in repeat echocardiographic imaging. He had a prolonged course in the ICU and hospital, but eventually made an essentially complete clinical recovery. CONCLUSION: As bedside echocardiographic technology becomes more rapidly and readily available, the rapid diagnosis of pulmonary embolism and use of thrombolytics during cardiopulmonary resuscitation may need to be more routinely considered a potential therapeutic adjunctive measure.

Longitudinal Changes in Multiple Biomarkers Are Associated with Cardiotoxicity in Breast Cancer Patients Treated with Doxorubicin, Taxanes, and Trastuzumab.

BACKGROUND: Biomarkers may play an important role in identifying patients at risk for cancer therapy cardiotoxicity. Our objectives were to define the patterns of change in biomarkers with cancer therapy and their associations with cardiotoxicity. METHODS: In a multicenter cohort of 78 breast cancer patients undergoing doxorubicin and trastuzumab therapy, 8 biomarkers were evaluated at baseline and every 3 months over a maximum follow-up of 15 months. These biomarkers, hypothesized to be mechanistically relevant to cardiotoxicity, included high-sensitivity cardiac troponin I (hs-cTnI), high-sensitivity C-reactive protein (hsCRP), N-terminal pro-B-type natriuretic peptide (NT-proBNP), growth differentiation factor 15 (GDF-15), myeloperoxidase (MPO), placental growth factor (PlGF), soluble fms-like tyrosine kinase receptor-1 (sFlt-1), and galectin 3 (gal-3). We determined if biomarker increases were associated with cardiotoxicity at the same visit and the subsequent visit over the entire course of therapy. Cardiotoxicity was defined by the Cardiac Review and Evaluation Criteria; alternative definitions were also considered. RESULTS: Across the entire cohort, all biomarkers except NT-proBNP and gal-3 demonstrated increases by 3 months; these increases persisted for GDF-15, PlGF, and hs-cTnI at 15 months. Increases in MPO, PlGF, and GDF-15 were associated with cardiotoxicity at the same visit [MPO hazard ratio 1.38 (95% CI 1.10-1.71), P = 0.02; PlGF 3.78 (1.30-11.0), P = 0.047; GDF-15 1.71 (1.15-2.55), P = 0.01] and the subsequent visit. MPO was robust to alternative outcome definitions. CONCLUSIONS: Increases in MPO are associated with cardiotoxicity over the entire course of doxorubicin and trastuzumab therapy. Assessment with PlGF and GDF-15 may also be of value. These findings motivate validation studies in additional cohorts.

Radiation-related heart and vascular disease.

Improvement in cancer therapy has led to increasing number of cancer survivors, some of whom have previously been treated with mediastinal radiation. Cardiac complication may manifest years after completion of radiation therapy. Hence long-term follow-up is essential in these patients. In this paper, we have discussed the short- and long-term cardiovascular side effects of radiation therapy.

Early recognition of apical ballooning syndrome by global longitudinal strain using speckle tracking imaging--the evil eye pattern, a case series.

We report 4 cases of patients diagnosed with stress-induced cardiomyopathy and the pattern of typical apical ballooning syndrome (ABS), who presented to our institution with chest pain, mildly elevated cardiac enzymes and ischemic electrocardiographic changes, found to have severe hypokinesis or akinesis of the mid to apical segments with dynamic basal segments on two-dimensional (2D) echocardiography along with a global longitudinal strain (GLS) pattern markedly different from the typical left anterior descending artery (LAD) myocardial infarction pattern. All of them had a similar GLS pattern on presentation, which was easy to recognize on the polar map the day of the event. Three of the patients underwent left heart catheterization and found to have nonobstructive coronary artery disease (CAD). We discuss the usefulness of early recognition of ABS using GLS images.

The short life of an aortic cusp aneurysm: a case report.

This report describes a 42-year-old man with a history of lymphoma who is admitted with symptoms of chest pain, ST elevation changes, and elevated troponins. Immediate bedside echocardiographic evaluation led to an aborted urgent coronary angiography and a diagnosis of presumed endocarditis. Transesophageal echocardiography (TTE) subsequently revealed an aortic noncoronary cusp aneurysm masking as vegetation. The rapid assessment by TTE and transesophageal echocardiogram prevented an alternate course for this patient's management. We reviewed the necessity of heart catheterization in patients with significantly elevated troponins, pericarditis symptoms, and the rare sighting of aortic valve cusp aneurysms.

Dexmedetomidine does not reduce atrial fibrillation after lung cancer surgery.

OBJECTIVE: To evaluate whether the use of intraoperative dexmedetomidine (DEX) during lung cancer surgery may reduce the incidence of postoperative atrial fibrillation (POAF). DESIGN: A retrospective study. SETTING: Academic hospital. PARTICIPANTS: Seven hundred three adult patients with non-small-cell lung cancer. MEASUREMENTS AND MAIN RESULTS: Patients younger than 18 years of age with a history of atrial fibrillation were excluded. Episodes of atrial fibrillation were identified from electronic medical records and consisted of cardiology consultations, electrocardiogram records, and use of anti-arrhythmic medications within the postoperative admission time. The Wilcoxon rank sum test was used to evaluate the difference in a continuous variable between patient groups. Fisher's exact test or the chi-square test was used to evaluate the association between 2 categorical variables. Logistic regression models were used for multivariate analysis. Overall POAF incidence was 136 of 703 (19.35%), with a mean onset of 3.01±2.03 days after surgery. Among patients, 204 (29.02%) received DEX intraoperatively. Male gender and age were strong predictors of POAF. POAF incidence was comparable between patients who were (n=93, 21.1%) and were not (n=43, 18.6%) treated with DEX (p=0.46). The mean onset time of arrhythmia was similar in both groups (DEX users: 2.93±2.49 days; non-DEX users: 3.05±1.79 days; p=0.146). CONCLUSION: These results were similar to those published elsewhere on POAF incidence and risk factors. This study could not confirm the hypothesis that the intraoperative use of DEX is associated with a reduced rate of POAF after thoracic surgery for lung cancer.

Preoperative Echocardiographic Parameters of Diastolic Dysfunction Did Not Provide a Predictive Value for Postoperative Atrial Fibrillation in Lung and Esophageal Cancer Surgery.

OBJECTIVE: To evaluate the predictive value of preoperative transthoracic echocardiography in the development of postoperative atrial fibrillation after non-cardiac thoracic surgery. DESIGN: This was a retrospective study. SETTING: Academic hospital. PARTICIPANTS: A total of 703 adult patients with non-small cell lung cancer. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Retrospective data of 177 non-cardiac thoracic surgical oncologic patients undergoing lung or esophageal cancer surgery with preoperative transthoracic echocardiograms (TTE) (within 30 days before surgery) were analyzed. The Wilcoxon rank sum test was used to evaluate the difference in continuous variables. Fisher's exact test or the chi-square test was used to evaluate the association between two categoric variables. Logistic regression models were used for multivariate analysis to include important and significant covariates. Among the demographic and echocardiographic variables measured age, systemic hypertension, e` septal, e` lateral and E/e` ratio were significantly different between patients who would develop postoperative atrial fibrillation (POAF) and those who did not. The logistic regression models only identify age as a predictor factor of POAF. CONCLUSIONS: These results were similar to those published elsewhere on POAF incidence and risk factors. The preoperative echocardiographic variables in this study did not provide predictive value for POAF in non-cardiac thoracic surgery.

Right ventricular function across the spectrum of health and disease.

Knowledge of right ventricular (RV) structure and function has historically lagged behind that of the left ventricle (LV). However, advancements in invasive and non-invasive evaluations, combined with epidemiological analyses, have advanced the current understanding of RV (patho)physiology across the spectrum of health and disease, and reinforce the centrality of the RV in contributing to clinical outcomes. In the healthy heart, ventricular-arterial coupling is preserved during rest and in response to increased myocardial demand (eg, exercise) due to substantial RV contractile reserve. However, prolonged exposure to increased myocardial demand, such as endurance exercise, may precipitate RV dysfunction, suggesting that unlike the LV, the RV is unable to sustain high levels of contractility for extended periods of time. Emerging data increasingly indicate that both LV and RV function contribute to clinical heart failure. Reductions in quality-of-life, functional capacity and overall clinical outcomes are worsened among patients with heart failure when there is evidence of RV dysfunction. In addition, the RV is adversely impacted by pulmonary vascular disease, and among affected patients, overall RV function differs based on mechanisms of the underlying pulmonary hypertension, which may result from variations in sarcomere function within RV cardiomyocytes.

Extensive Painless Aortic Dissection in a Patient With Breast Cancer.

This case illustrates the unusual clinical presentation and natural progression of type A aortic dissection, found incidentally on echocardiogram in a patient with breast cancer. Possible association of tyrosine kinase inhibitor with aortic dissection is reviewed in the light of this case.

Circulating microRNAs and Cytokines as Prognostic Biomarkers for Doxorubicin-Induced Cardiac Injury and for Evaluating the Effectiveness of an Exercise Intervention.

PURPOSE: To define a set of biomarkers that can be used to identify patients at high risk of developing late doxorubicin (DOX)-induced cardiac morbidity with the goal of focused monitoring and early interventions. EXPERIMENTAL DESIGN: Mice received phosphate buffered saline or DOX 2.5 mg/kg 2x/week for 2 weeks. Blood samples were obtained before and after therapy for quantification of miRNAs (6 and 24 hours), cytokines (24 hours), and troponin (24 hours, 4 and 6 weeks). Cardiac function was evaluated using echocardiography before and 24 hours after therapy. To assess the effectiveness of exercise intervention in preventing DOX-induced cardiotoxicity blood samples were collected from mice treated with DOX or DOX + exercise. Plasma samples from 13 DOX-treated patients with sarcoma were also evaluated before and 24 hours after therapy. RESULTS: Elevations in plasma miRNA-1, miRNA-499 and IL1α, IL1ß, and IL6 were seen in DOX-treated mice with decreased ejection fraction and fractional shortening 24 hours after DOX therapy. Troponin levels were not elevated until 4 weeks after therapy. In mice treated with exercise during DOX, there was no elevation in these biomarkers and no change in cardiac function. Elevations in these biomarkers were seen in 12 of 13 patients with sarcoma treated with DOX. CONCLUSIONS: These findings define a potential set of biomarkers to identify and predict patients at risk for developing acute and late cardiovascular diseases with the goal of focused monitoring and early intervention. Further studies are needed to confirm the predictive value of these biomarkers in late cardiotoxicity.