br Echocardiography parameters br As described previously ca
As described previously, cardiac (dys)function was evalu-ated using echocardiography.9 In short, all image acquisi-tion and analysis was performed by a central reading lab
Fig. 1. Example of the contouring of the coronary ar-teries. The LV was contoured using a multiatlas automatic segmentation tool based on the delineations by Feng et al.13 The contouring of the coronary arteries, including the left main coronary artery (purple), left anterior descending coronary artery (orange), and circumflex coro-nary artery (green) and right coronary artery (not shown in this figure) was done manually. Abbreviations: LA Z left atrium; LV Z left ventricle; RA Z right atrium; RV Z right ventricle.
(Groningen Imaging Core Laboratory) with Vivid E9 ul-trasound equipment (GE, Horten, Norway), based on a predefined imaging and measurement protocol. All mea-surements were performed in accordance with the guide-lines of the European Association of Cardiovascular Imaging/American Society of Echocardiography (ASE).15
Systolic function was evaluated in 2 ways, first by the LVEF, which was measured by the biplane method of disks summation (modified Simpson’s rule). In cases where the image quality was too low to reliably determine the endo-cardial border, an estimation of LVEF was given by an experienced ultrasound technician. The LVEF was analyzed for 107 patients. Abnormal LVEF was defined as an LVEF <54%, according to the European Association of Cardio-vascular Imaging/ASE guidelines.15 Additionally, GLS was determined as another measure of systolic function. For this reason, the echocardiograms were retrospectively analyzed for the GLS of the LV, using automated 2-dimensional speckle-tracking with TomTec Imaging Systems GmbH Arena 2 (Munich, Germany). For this analysis, we excluded all echocardiographies that were evaluated using eyeballing (n Z 38), because the image quality was too low for a reliable assessment of this endpoint. r> The remaining 71 echocardiographies were measured using Simpson’s biplane method. Of those, 19 were excluded because of persistent inadequate tracking of GLS BODIPY505 / 515 or incorrect tracing of the apex. Furthermore, the echocardiographies were checked for reproducibility of
Volume 104 Number 2 2019 Cardiac function after breast irradiation 395
GLS by analyzing inter- and intraobserver variability. The
interclass correlation coefficient (ICC) was determined and accepted if greater than 0.6.16,17 As a result, the GLS of the
LV diastolic dysfunction was analyzed for 109 patients and defined by e’ at the lateral and septal region, where e’ represents the relaxation velocity of the myocardium in early diastole. Diastolic dysfunction was defined as e’ lateral or e’ septal at 2.5% below the normal range for each age group, according to the European Association of Echocardiography/ASE.18 By calculating the average of e’ septal and e’ lateral together, a continuous variable was created.19
Patient characteristics (including cardiovascular risk factors [diabetes mellitus, hypertension, dyslipidemia, smoking, and body mass index], cardiac diseases [heart failure, ar-rhythmias, non-rheumatic valve disorder, and ischemic heart disease]), tumor characteristics and information about BC systemic treatment (chemotherapy, endocrine therapy and/or trastuzumab) and RT were described at the time of diagnosis and if applicable at the time of echocardiography using descriptive statistics. Clinical factors at time of diagnosis were included in the analysis because pre-existing cardiac conditions in combination with RT were found to increase the risk of subsequent cardiac events.5,6 Arrhythmias included supraventricular tachycardia, ven-tricular paroxysmal tachycardia, and/or atrial fibrillation. Nonrheumatic valve disorder included aortic stenosis and/ or mitral valve insufficiency. Ischemic heart diseases included coronary atherosclerosis, myocardial infarction, and/or angina pectoris. Using DVH data from each patient’s RT plan, we first calculated the mean dose, maximum dose, and mean V(x) in bins of 5 Gy, where V(x) refers to the relative volume (in percentage) of the cardiac substructures that received a dose of x Gy. Both systolic and diastolic function were defined as binary variables and as continuous variables, whenever appropriate.
The first step in identifying associations between patient characteristics, risk factors, and treatment characteristics and the endpoints of systolic and diastolic function was a preselection based on intervariable correlation to reduce the number of variables. If the Pearson correlation of 2 vari-ables was larger than 0.80, the variable with the strongest univariable association with the endpoint was selected.20 Second, univariable and multivariable stepwise forward selection was used to select the most important risk factors. The entire variable selection procedure (preselection and forward selection) was repeated on 1000 bootstrapped samples of a size equal to the original study population and drawn with replacement. The resulting most frequently