Cancer Therapeutics-related Cardiac Dysfunction Research Articles

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.

Prognostic Significance of New-Onset Atrial Fibrillation in Patients With Non-Hodgkin's Lymphoma Treated With Anthracyclines

Cancer therapeutics-related cardiac dysfunction induced by anthracycline is highly problematic, and its early recognition is of importance. Atrial fibrillation (AF) is sometimes seen after anthracycline chemotherapy. We aimed to test whether new-onset AF predicts anthracycline-induced heart failure. We prospectively studied 249 lymphoma patients who received anthracyclines. The patients were followed up with a frequent electrocardiographic examination. Fifteen patients (6%) newly developed AF after the chemotherapy, and during a mean follow-up of 34months, they had a higher incidence of acute heart failure (40% vs 3.8%; p <0.001) and greater all-cause mortality (60% vs 14.1%; p <0.001) than those without AF. The onset of AF preceded the development of heart failure by a mean of 2.4months. New-onset AF was independently associated with both acute heart failure (hazard ratio 12.78; p <0.001) and all-cause mortality (hazard ratio 4.77; p <0.001). The cumulative anthracycline dose did not differ between the patients with and without heart failure, yet it was another independent predictor of the mortality. In conclusion, new-onset AF may predict unfavorable outcomes after anthracycline chemotherapy in patients with malignant lymphoma.

Cardiovascular effects of the addition of nilotinib to standard therapy for acute myeloid leukemia.

e18505 Background: Angina, arrhythmias and QT prolongation have been cardiac adverse effects reported in clinical trials with nilotinib, which inhibits the tyrosine kinase activity of BCR-ABL and KIT. The objective of this study was to assess cardiac events in acute myeloid leukemia (AML) patients treated with standard therapy (an anthracycline plus cytarabine or 7+3) versus KIT positive AML patients treated with 7+3 plus nilotinib as part of a clinical trial. Methods: After IRB approval, 100 consecutive patients treated for newly diagnosed AML at Mayo Clinic who consented to the use of their medical records for research were identified and a retrospective chart review performed. The primary endpoint was heart failure defined by the modified Framingham criteria. Secondary endpoints included cancer therapeutics-related cardiac dysfunction (CTRCD) defined as a drop in ejection fraction of > 10% to < 53%, arrhythmias defined as a new rhythm abnormality other than sinus bradycardia or tachycardia resulting in a change to therapy or transfer to a higher level of care, and acute coronary syndromes (ACS) diagnosed by a cardiologist. Between group differences were assessed using t-tests, Wilcoxon tests, or Fisher’s exact tests. Results: Thirteen patients (13%) received nilotinib plus 7+3 and 87 patients (87%) received 7+3. No patients had a prior exposure to nilotinib. Median follow-up was 73 weeks (55-87) in the nilotinib plus 7+3 group and 83 weeks (30-139) in the 7+3 group. Groups were similar with respect to age, sex, comorbidities and baseline medical therapy. No significant difference was observed between those who did versus did not receive nilotinib respectively in the incidence of heart failure (8% vs. 14%), CTRCD (15% vs. 16%), ACS (0 vs. 3%) and arrhythmias (0 vs. 16%)(all p > 0.1). Conclusions: The addition of nilotinib to standard therapy for AML was not associated with an increase in cardiac events for at least 1 year of follow up. This finding is important as the use of tyrosine kinase inhibitors in combination with other chemotherapeutic agents may increase in the future with personalized medicine. However, the follow-up was insufficient to detect late onset cardiac toxicity and studies with longer follow-up are needed.

Noninvasive Measures of Ventricular-Arterial Coupling and Circumferential Strain Predict Cancer Therapeutics–Related Cardiac Dysfunction

ObjectivesThis study sought to determine the relationships between echocardiography-derived measures of myocardial mechanics and cancer therapeutics–related cardiac dysfunction (CTRCD). BackgroundDoxorubicin and trastuzumab are highly effective breast cancer therapies, but have a substantial risk of CTRCD. There is a critical need for the early detection of patients at increased risk of toxicity. MethodsWe performed a prospective, longitudinal cohort study of breast cancer participants undergoing doxorubicin and/or trastuzumab therapy. Echocardiography was performed prior to therapy initiation (baseline) and at standardized follow-up intervals during and after completion of therapy. Ejection fraction (EF), strain, strain rate, and ventricular-arterial coupling (effective arterial elastance [Ea]/end-systolic elastance [Eessb]) were quantitated. CTRCD was defined as a ≥10% reduction in EF from baseline to <50%. Multivariable logistic regression models were used to determine the associations between baseline levels and changes from baseline in echocardiographic measures and CTRCD. Receiver-operating characteristic curves were used to evaluate the predictive ability of these measures. ResultsIn total, 135 participants contributed 517 echocardiograms to the analysis. Over a median follow-up time of 1.9 years (interquartile range: 0.9 to 2.4 years), 21 participants (15%) developed CTRCD. In adjusted models, baseline levels and changes in Ea/Eessb, circumferential strain, and circumferential strain rate were associated with 21% to 38% increased odds of CTRCD (p < 0.001). Changes in longitudinal strain (p = 0.037), radial strain (p = 0.015), and radial strain rate (p = 0.006) were also associated with CTRCD. Ea/Eessb (area under the curve: 0.703; 95% confidence interval: 0.583 to 0.807) and circumferential strain (area under the curve: 0.655; 95% confidence interval: 0.517 to 0.767) demonstrated the greatest predictive utility. Sensitivity analyses using an alternative CTRCD definition did not impact our results. ConclusionsOver an extended follow-up time, ventricular-arterial coupling and circumferential strain were strongly predictive of CTRCD. Our findings suggest a noninvasive strategy to identify high-risk patients prior to, during, and after cardiotoxic cancer therapy.

Feasibility of Echocardiographic Techniques to Detect Subclinical Cancer Therapeutics–Related Cardiac Dysfunction among High-Dose Patients When Compared with Cardiac Magnetic Resonance Imaging

Cardiac magnetic resonance imaging (CMR) is the gold standard for the quantification of global and regional myocardial function and can detect subclinical myocardial dysfunction in anthracycline-induced cardiomyopathy. The aim of this study was to ascertain reliable echocardiographic parameters that can be used for the early identification of cancer therapeutics-related cardiac dysfunction, compared with CMR. Fifty-seven pediatric cancer survivors, 10 to 42years of age, with cumulative anthracycline doses≥200mg/m(2), were studied with transthoracic echocardiography and CMR 2.4 to 26.9years after chemotherapy. Three-dimensional echocardiography had the highest sensitivity in identifying subjects with CMR-derived ejection fractions<55%. Subjects with end-systolic volume index values>29mL/m(2) were more likely to have CMR-derived ejection fractions<55%. Three-dimensional speckle-tracking echocardiographic peak global longitudinal strain magnitude<-17.5% best identified subjects with abnormal peak midwall longitudinal strain magnitude by CMR. A decrease in early atrial myocardial velocity of <10cm/sec at the interventricular septum also identified subjects with lower average peak midwall longitudinal strain and peak midwall circumferential strain magnitudes by CMR. Three-dimensional echocardiographic ejection fraction<55%, end-systolic volume index>29mL/m(2), three-dimensional speckle-tracking echocardiographic peak global longitudinal strain magnitude<-17.5%, and a decrease in early atrial myocardial velocity at the interventricular septum of <10cm/sec by Doppler tissue imaging are the most sensitive transthoracic echocardiographic parameters to identify subjects with subclinical myocardial dysfunction by CMR.

Cardiotoxicity Associated with Trastuzumab in Breast Cancer Patients: Definition of Cancer Therapeutics-Related Cardiac Dysfunction (CTRCD)

Cardiotoxicity Associated with Trastuzumab in Breast Cancer Patients: Definition of Cancer Therapeutics-Related Cardiac Dysfunction (CTRCD)

Strategies for early detection of cardiotoxicities from anticancer therapy in adults: evolving imaging techniques and emerging serum biomarkers.

Significant advances have been made in detecting cancer therapeutics-related cardiac dysfunction with serum biomarkers, cardiovascular MRI, echocardiography and multi-modality approaches. Serum biomarkers, notably cardiac troponins and natriuretic peptides, have been evaluated for their prognostic ability in predicting left ventricular dysfunction. Imaging modalities, such as cardiovascular MRI and echocardiography, have been used for cardiac surveillance of patients with cancer undergoing chemotherapy. Developments in imaging, specifically myocardial deformation imaging, also known as strain, have been shown to be sensitive tools in detecting early changes in cardiac function. This review aims to synthesize the evidence that supports emerging serum biomarkers and complementary imaging modalities that continue to enhance the detection of cancer therapeutics-related cardiac dysfunction.

Strain imaging to detect cancer therapeutics-related cardiac dysfunction: are we there yet?

Robert & Suzanne Tomsich Department of Cardiovascular Medicine, Cleveland Clinic, 9500 Euclid Ave./J1-5 Cleveland, OH 44195, USA *Author for correspondence: Tel.: +1 216 444 8429; Fax: +1 216 445 6164; colliep@ccf.org

Chemotherapy Related Severe Cardiac Dysfunction - Case Report.

Cardiotoxicity is the most important side effect of cancer therapy resulting in increased patient morbidity and mortality, therefore understanding its occurrence mechanism and a correct and early diagnosis are essential for patients at risk of irreversible heart failure. We present the case of a patient who developed cancer therapeutics-related cardiac dysfunction, emphasizing the importance of regular echocardiographic evaluation for early detection of subclinical cardiac dysfunction and further cardiac monitoring. More sensitive parameters should be used to predict cardiotoxicity because the probability of cardiac function recovery diminishes in time, despite optimal heart failure treatment.