Methods
The study population is part of the Israel Cardio-Oncology Registry (ICOR) – a prospective registry enrolling all patients evaluated in the cardio-oncology clinic at Tel Aviv Sourasky Medical Center. All patients signed an informed consent at the first visit in the clinic and are then followed prospectively. The registry was approved by the local ethics committee (Identifier: 0228-16-TLV) and is registered in clinicaltrials.gov (Identifier: NCT02818517).
This cohort evaluated patients diagnosed with breast cancer planned for ANT therapy. All patients underwent at least 2 echocardiographic evaluations, including GLS; at baseline before chemotherapy (T1) and during Doxorubicin (a type of ANT) therapy (T2). A 3rdechocardiography exam (T3), was performed within 3 months after the completion of Doxorubicin therapy.
The exclusion criteria included LVEF<53% at T1 and significant GLS relative reduction≥15% at T2.
Diastolic strain was measured by the time of lengthening (Dst) (ms) of the myocardium as specified in the next paragraph (Figure 1). The change in Dst was assessed between T1 to T2 and its association for GLS reduction in T3 was evaluated. A clinically significant reduction in GLS was considered as a relative reduction of ≥15% from T1 to T3, adhered to the standard benchmark set by previous studies [15].
Three standard apical views (4-chamber, 2-chamber, and 3-chamber) were recorded using a General Electric system, model Vivid S70 echocardiogram and were performed by the same vendor, technician and interpreting cardiologist. Routine Left ventricle (LV) echocardiographic parameters included LV diameters, and LVEF [16]. Early trans-mitral flow velocity (E), late atrial contraction (A) velocity, deceleration time (DT) and early diastolic mitral annular velocity (medial and lateral e’) were measured in the apical 4-chamber view [17]. The peak E/e’ ratio was calculated (septal, lateral and average). Images were acquired using high frame rate (>50 frames/s) [18], and thereafter stored digitally for offline analysis. GLS was measured using 2D-STE software and tracking within an approximately 5 mm wide region of interest. An end-systolic frame was used to initialize LV boundaries which were then automatically tracked throughout the cardiac cycle. Manual corrections were performed to optimize boundary tracking as needed. Optimization of images for endocardial visualization through adjustment of gain, compress, and time-gain compensation controls was done prior to acquisition. Dst was evaluated by measuring manually the time of lengthening (ms) of the myocardium during diastole. According to past studies, showing significant association between diastolic strain rate and the time constant of LV relaxation [11], we evaluated the Dst from the point of aortic valve closure (AVC) throughout the isovolumic relaxation time and early diastolic, until the plateau of the curve (Fig. 1), Dst was assessed in three apical views (2, 3 and 4-chamber), with 6 segments measured per each view, with a total of 18 segments per each exam. Dst change between T1 and T2 was assessed according to the following segments: Average, Anterior, Inferior, Lateral, Septal, Anteroseptal, Posterior, Apex, Mid and Base, as specified in Table 2.