Juan Carlos Plana

Expert consensus for multimodality imaging evaluation of adult patients during and after cancer therapy: a report from the American Society of Echocardiography and the European Association of Cardiovascular Imaging.

Cardiac dysfunction resulting from exposure to cancer therapeutics was first recognized in the 1960s, with the widespread introduction of anthracyclines into the oncologic therapeutic armamentarium. Heart failure (HF) associated with anthracyclines was then recognized as an important side effect. As a result, physicians learned to limit their doses to avoid cardiac dysfunction. Several strategies have been used over the past decades to detect it. Two of them evolved over time to be very useful: endomyocardial biopsies and monitoring of left ven- tricular (LV) ejection fraction (LVEF) by cardiac imaging. Examination of endomyocardial biopsies proved to be the most sensitive and spe- cific parameter for the identification of anthracycline-induced LV dysfunction and became the gold standard in the 1970s. However, the interest in endomyocardial biopsy has diminished over time because of the reduction in the cumulative dosages used to treat ma- lignancies, the invasive nature of the procedure, and the remarkable progress made in noninvasive cardiac imaging. The noninvasive evaluation of LVEF has gained importance, and notwithstanding the limitations of the techniques used for its calculation, has emerged as the most widely used strategy for monitoring the changes in cardiac function, both during and after the administration of potentially car- diotoxic cancer treatment.

Assessment of Echocardiography and Biomarkers for the Extended Prediction of Cardiotoxicity in Patients treated with Anthracyclines, Taxanes and Trastuzumab

Background—Because cancer patients survive longer, the impact of cardiotoxicity associated with the use of cancer treatments escalates. The present study investigates whether early alterations of myocardial strain and blood biomarkers predict incident cardiotoxicity in patients with breast cancer during treatment with anthracyclines, taxanes, and trastuzumab. Methods and Results—Eighty-one women with newly diagnosed human epidermal growth factor receptor 2–positive breast cancer, treated with anthracyclines followed by taxanes and trastuzumab were enrolled to be evaluated every 3 months during their cancer therapy (total of 15 months) using echocardiograms and blood samples. Left ventricular ejection fraction, peak systolic longitudinal, radial, and circumferential myocardial strain were calculated. Ultrasensitive troponin I, N-terminal pro–B-type natriuretic peptide, and the interleukin family member (ST2) were also measured. Left ventricular ejection fraction decreased (64 ± 5% to 59 ± 6%; P<0.0001) over 15 months. Twenty-six patients (32%, [22%–43%]) developed cardiotoxicity as defined by the Cardiac Review and Evaluation Committee Reviewing Trastuzumab; of these patients, 5 (6%, [2%–14%]) had symptoms of heart failure. Peak systolic longitudinal myocardial strain and ultrasensitive troponin I measured at the completion of anthracyclines treatment predicted the subsequent development of cardiotoxicity; no significant associations were observed for left ventricular ejection fraction, N-terminal pro–B-type natriuretic peptide, and ST2. Longitudinal strain was <19% in all patients who later developed heart failure. Conclusions—In patients with breast cancer treated with anthracyclines, taxanes, and trastuzumab, systolic longitudinal myocardial strain and ultrasensitive troponin I measured at the completion of anthracyclines therapy are useful in the prediction of subsequent cardiotoxicity and may help guide treatment to avoid cardiac side-effects.

Reproducibility of Echocardiographic Techniques for Sequential Assessment of Left Ventricular Ejection Fraction and Volumes Application to Patients Undergoing Cancer Chemotherapy

OBJECTIVES The aim of this study was to identify the best echocardiographic method for sequential quantification of left ventricular (LV) ejection fraction (EF) and volumes in patients undergoing cancer chemotherapy. BACKGROUND Decisions regarding cancer therapy are based on temporal changes of EF. However the method for EF measurement with the lowest temporal variability is unknown. METHODS We selected patients in whom stable function in the face of chemotherapy for breast cancer was defined by stability of global longitudinal strain (GLS) at up to 5 time points (baseline, 3, 6, 9, and 12 months). In this way, changes in EF were considered to reflect temporal variability of measurements rather than cardiotoxicity. A comprehensive echocardiogram consisting of 2-dimensional (2D) and 3-dimensional (3D) acquisitions with and without contrast administration was performed at each time point. Stable LV function was defined as normal GLS (≤-16.0%) at each examination. The EF and volumes were measured with 2D-biplane Simpsons method, 2D-triplane, and 3-dimensional echocardiography (3DE) by 2 investigators blinded to any clinical data. Inter-, intra-, and test-retest variability were assessed in a subgroup. Variability was assessed by analysis of variance and compared with Levenes or t test. RESULTS Among 56 patients (all female, 54 ± 13 years of age), noncontrast 3D EF, end-diastolic volume, and end-systolic volume had significantly lower temporal variability than all other methods. Contrast only decreased the temporal variability of LV end-diastolic volume measurements by the 2D biplane method. Our data suggest that a temporal variability in EF of 0.06 might occur with noncontrast 3DE due to physiological differences and measurement variability, whereas this might be >0.10 with 2D methods. Overall, 3DE also had the best intra- and inter-observer as well as test-retest variability. CONCLUSIONS Noncontrast 3DE was the most reproducible technique for LVEF and LV volume measurements over 1 year of follow-up.

Clinical ResearchCardiac ImagingReproducibility of Echocardiographic Techniques for Sequential Assessment of Left Ventricular Ejection Fraction and Volumes: Application to Patients Undergoing Cancer Chemotherapy

OBJECTIVES The aim of this study was to identify the best echocardiographic method for sequential quantification of left ventricular (LV) ejection fraction (EF) and volumes in patients undergoing cancer chemotherapy. BACKGROUND Decisions regarding cancer therapy are based on temporal changes of EF. However the method for EF measurement with the lowest temporal variability is unknown. METHODS We selected patients in whom stable function in the face of chemotherapy for breast cancer was defined by stability of global longitudinal strain (GLS) at up to 5 time points (baseline, 3, 6, 9, and 12 months). In this way, changes in EF were considered to reflect temporal variability of measurements rather than cardiotoxicity. A comprehensive echocardiogram consisting of 2-dimensional (2D) and 3-dimensional (3D) acquisitions with and without contrast administration was performed at each time point. Stable LV function was defined as normal GLS (≤-16.0%) at each examination. The EF and volumes were measured with 2D-biplane Simpsons method, 2D-triplane, and 3-dimensional echocardiography (3DE) by 2 investigators blinded to any clinical data. Inter-, intra-, and test-retest variability were assessed in a subgroup. Variability was assessed by analysis of variance and compared with Levenes or t test. RESULTS Among 56 patients (all female, 54 ± 13 years of age), noncontrast 3D EF, end-diastolic volume, and end-systolic volume had significantly lower temporal variability than all other methods. Contrast only decreased the temporal variability of LV end-diastolic volume measurements by the 2D biplane method. Our data suggest that a temporal variability in EF of 0.06 might occur with noncontrast 3DE due to physiological differences and measurement variability, whereas this might be >0.10 with 2D methods. Overall, 3DE also had the best intra- and inter-observer as well as test-retest variability. CONCLUSIONS Noncontrast 3DE was the most reproducible technique for LVEF and LV volume measurements over 1 year of follow-up.

Expert consensus for multimodality imaging evaluation of adult patients during and after cancer therapy: a report from the American Society of Echocardiography and the European Association of Cardiovascular Imaging

### A. Definition, classification, and mechanisms of toxicity Cardiac dysfunction resulting from exposure to cancer therapeutics was first recognized in the 1960s, with the widespread introduction of anthracyclines into the oncological therapeutic armamentarium.1 Heart failure (HF) associated with anthracyclines was then recognized as an important side effect. As a result, physicians learned to limit their doses to avoid cardiac dysfunction.2 Several strategies have been used over the past decades to detect it. Two of them evolved over time to be very useful: endomyocardial biopsies and monitoring of left ventricular (LV) ejection fraction (LVEF) by cardiac imaging. Examination of endomyocardial biopsies proved to be the most sensitive and specific parameter for the identification of anthracycline-induced LV dysfunction and became the gold standard in the 1970s. However, the interest in endomyocardial biopsy has diminished over time because of the reduction in the cumulative dosages used to treat malignancies, the invasive nature of the procedure, and the remarkable progress made in non-invasive cardiac imaging. The non-invasive evaluation of LVEF has gained importance, and notwithstanding the limitations of the techniques used for its calculation, has emerged as the most widely used strategy for monitoring the changes in cardiac function, both during and after the administration of potentially cardiotoxic cancer treatment.3–5 The timing of LV dysfunction can vary among agents. In the case of anthracyclines, the damage occurs immediately after the exposure;6 for others, the time frame between drug administration and detectable cardiac dysfunction appears to be more variable. Nevertheless, the heart has significant cardiac reserve, and the expression of damage in the form of alterations in systolic or diastolic parameters may not be overt until a substantial amount of cardiac reserve has been exhausted. Thus, cardiac damage may not become apparent until years or even decades after receiving the cardiotoxic treatment. This is particularly applicable to …

Heart failure associated with sunitinib malate: a multitargeted receptor tyrosine kinase inhibitor.

Sunitinib malate is a novel multitargeted receptor tyrosine kinase inhibitor with established efficacy in the treatment of metastatic renal cell carcinoma and imatinib‐resistant gastrointestinal stromal tumor. This report describes the development of heart failure in cancer patients who received this novel agent.

Relative apical sparing of longitudinal strain using two-dimensional speckle-tracking echocardiography is both sensitive and specific for the diagnosis of cardiac amyloidosis

Background The diagnosis of cardiac amyloidosis (CA) is challenging owing to vague symptomatology and non-specific echocardiographic findings. Objective To describe regional patterns in longitudinal strain (LS) using two-dimensional speckle-tracking echocardiography in CA and to test the hypothesis that regional differences would help differentiate CA from other causes of increased left ventricular (LV) wall thickness. Methods and results 55 consecutive patients with CA were compared with 30 control patients with LV hypertrophy (n=15 with hypertrophic cardiomyopathy, n=15 with aortic stenosis). A relative apical LS of 1.0, defined using the equation (average apical LS/(average basal LS + mid-LS)), was sensitive (93%) and specific (82%) in differentiating CA from controls (area under the curve 0.94). In a logistic regression multivariate analysis, relative apical LS was the only parameter predictive of CA (p=0.004). Conclusions CA is characterised by regional variations in LS from base to apex. A relative ‘apical sparing’ pattern of LS is an easily recognisable, accurate and reproducible method of differentiating CA from other causes of LV hypertrophy.

Expert Consensus for Multi-Modality Imaging Evaluation of Cardiovascular Complications of Radiotherapy in Adults: A Report from the European Association of Cardiovascular Imaging and the American Society of Echocardiography

Cardiac toxicity is one of the most concerning side effects of anti-cancer therapy. The gain in life expectancy obtained with anti-cancer therapy can be compromised by increased morbidity and mortality associated with its cardiac complications. While radiosensitivity of the heart was initially recognized only in the early 1970s, the heart is regarded in the current era as one of the most critical dose-limiting organs in radiotherapy. Several clinical studies have identified adverse clinical consequences of radiation-induced heart disease (RIHD) on the outcome of long-term cancer survivors. A comprehensive review of potential cardiac complications related to radiotherapy is warranted. An evidence-based review of several imaging approaches used to detect, evaluate, and monitor RIHD is discussed. Recommendations for the early identification and monitoring of cardiovascular complications of radiotherapy by cardiac imaging are also proposed.

Effect of statin therapy on the risk for incident heart failure in patients with breast cancer receiving anthracycline chemotherapy: an observational clinical cohort study.

OBJECTIVES The aim of this study was to evaluate the effect of continuous statin treatment on new-onset heart failure (HF) in patients with breast cancer receiving anthracycline-based chemotherapy. BACKGROUND In vitro and animal model experimental studies have reported that statins prevent doxorubicin-induced cardiotoxicity. METHODS A total of 628 women with newly diagnosed breast cancer (mean age 51.5 ± 10.8 years) treated with anthracycline were retrospectively identified and studied. The primary outcome (incident HF hospitalization) was compared in propensity-matched patients receiving uninterrupted statin therapy through the follow-up period of 2.55 ± 1.68 years and their counterparts not receiving continuous statin therapy. RESULTS After propensity matching (2:1), the 67 patients (10.7%) receiving uninterrupted statin therapy were combined with 134 controls. New-onset HF was observed in 67 of the 201 matched patients. Multivariate-matched Cox regression analysis showed a significantly lower hazard ratio [HR] of 0.3 (95% confidence interval [CI]: 0.1 to 0.9; p = 0.03) for patients taking uninterrupted statin therapy. Cardiotoxicity risk factors at the time of cancer diagnosis (HR: 5.0; 95% CI: 2.2 to 11.1; p < 0.001), baseline ejection fraction <55% (HR: 2.7; 95% CI: 1.2 to 6.3; p = 0.02), and trastuzumab use (HR: 3.0; 95% CI: 1.3 to 7.2; p = 0.01) were predictors of incident HF. CONCLUSIONS In this analysis of female patients with breast cancer treated with anthracycline chemotherapy, statin use was associated with a lower risk for incident HF. This finding is consistent with prior animal studies and warrants further investigation through prospective randomized clinical trials.

Screening Adult Survivors of Childhood Cancer for Cardiomyopathy: Comparison of Echocardiography and Cardiac Magnetic Resonance Imaging

PURPOSE To compare two-dimensional (2D) echocardiography, the current method of screening for treatment-related cardiomyopathy recommended by the Childrens Oncology Group Guidelines, to cardiac magnetic resonance (CMR) imaging, the reference standard for left ventricular (LV) function. PATIENTS AND METHODS Cross-sectional, contemporaneous evaluation of LV structure and function by 2D and three-dimensional (3D) echocardiography and CMR imaging in 114 adult survivors of childhood cancer currently median age 39 years (range, 22 to 53 years) exposed to anthracycline chemotherapy and/or chest-directed radiation therapy. RESULTS In this survivor population, 14% (n = 16) had an ejection fraction (EF) less than 50% by CMR. Survivors previously undiagnosed with cardiotoxicity (n = 108) had a high prevalence of EF (32%) and cardiac mass (48%) that were more than two standard deviations below the mean of normative CMR data. 2D echocardiography overestimated the mean EF of this population by 5%. Compared with CMR, 2D echocardiography (biplane method) had a sensitivity of 25% and a false-negative rate of 75% for detection of EF less than 50%, although 3D echocardiography had 53% and 47%, respectively. Twelve survivors (11%) had an EF less than 50% by CMR but were misclassified as ≥ 50% (range, 50% to 68%) by 2D echocardiography (biplane method). Detection of cardiomyopathy was improved (sensitivity, 75%) by using a higher 2D echocardiography cutoff (EF < 60%) to detect an EF less than 50% by the reference standard CMR. CONCLUSION CMR identified a high prevalence of cardiomyopathy among adult survivors previously undiagnosed with cardiac disease. 2D echocardiography demonstrated limited screening performance. In this high-risk population, survivors with an EF 50% to 59% by 2D echocardiography should be considered for comprehensive cardiac assessment, which may include CMR.