Study Population

We prospectively enrolled 88 patients (mean age, 45 ± 11 years; 48 men) who underwent BMT from October 2013 to December 2015 in the transplantation center of the hematologic department of the Second Propedeutic Department of Internal Medicine, University of Athens. Diagnoses included non-Hodgkin’s lymphoma (NHL) in 44 patients, acute myeloid leukemia (AML) in 34 patients, and chronic myeloid leukemia (CML) in 10 patients. Before BMT, patients with NHL received conditioning therapy with BEAM (carmustine 300 mg/m ² /day for 1 day, etoposide 200 mg/m ² /day for 4 days, cytarabine 400 mg/m ² /day for 4 days, and melphalan 140 mg/m ² /day for 1 day), and patients with AML or CML received therapy with Bu-Thio-Flu (busulfan 3.2 mg/kg/day for 3 days, fludarabine 25 mg/m ² /day for 5 days, and thiotepa 5 mg/kg/day on days 5 and 6). All patients had also received chemotherapy before the decision to perform BMT and before conditioning treatment with either BEAM or Bu-Thio-Flu. Patients with NHL had received cyclophosphamide 750 mg/m ² , doxorubicin 50 mg/m ² , vincristine 2 mg/m ² , and rituximab 375 mg/m ² on day 1 and oral prednisolone 40 mg/m ² on days 1 to 5 for six cycles and etoposide 50 mg/m ² for 4 days, methylprednisolone 500 mg for 5 days, cytarabine 2 g/m ² for 1 day, and cisplatin 25 mg/m ² for 4 days for three cycles. Patients with AML had received idarubicin 12 mg/m ² for 3 days and cytarabine 2 g/m ² for 5 days. Patients with CML had received imatinib 400 mg/day. The mean time from initial treatment before the decision to perform BMT until administration of conditioning treatment for BMT preparation (BEAM or Bu-Thio-Flu) was 5 ± 3 months. Thus, 78 of 88 patients (89%) had received anthracyclines before chemotherapy regimens for BMT. Exclusion criteria were history of coronary artery disease (angina, ST-segment or non-ST-segment elevation myocardial infarction), atrial fibrillation, presence of wall motion abnormalities, LVEF ≤ 50%, presence of left ventricular (LV) hypertrophy on electrocardiography or echocardiography, uncontrolled hypertension, primary cardiomyopathy, and moderate or severe valvular heart disease. Ten patients with two or more risk factors for coronary artery disease underwent dobutamine stress echocardiography to exclude myocardial ischemia that could contribute to subclinical LV or right ventricular (RV) dysfunction. Patients who failed to attend one of the follow-up visit for the echocardiography study were not included in the analysis. Informed consent was obtained from each patient. The study protocol conformed to the ethical guidelines of the 1975 Declaration of Helsinki, as reflected in a priori approval by the institution’s human research committee.

Standard Echocardiography

Echocardiography was performed before (baseline) the initiation of conditioning chemotherapy (BEAM or Bu-Thio-Flu) before BMT and 1, 3, 6, and 12 months after BMT using a Vivid 7 ultrasound system (GE Vingmed Ultrasound, Horten, Norway). All studies were digitally stored using a computerized station (EchoPAC, version 201 6.3, GE Vingmed Ultrasound, Horten, Norway) and were analyzed by two observers blinded to clinical and laboratory data. Two patients had inadequate images for analysis and thus were excluded from the study.

All measurements were performed according to the current guidelines of the American Society of Echocardiography and the European Association of Cardiovascular Imaging. Interventricular septal and posterior wall thickness and LV end-diastolic and end-systolic diameters were measured. End-diastolic and end-systolic areas were measured from the apical four-chamber and two-chamber views for the calculation of LVEF using the modified biplane Simpson method. Assessment of diastolic function was based on pulsed-wave Doppler of transmitral flow, the E and A waves, and deceleration time. Doppler tissue imaging (DTI) pulsed-wave velocities were recorded from the apical four-chamber views. Mean S′ and mean E′ represent the mean systolic and mean early diastolic velocities derived from the lateral mitral annulus and basal interventricular septum, and the E/mean E′ ratio was also calculated. Midcavity transversal end-diastolic RV diameter was measured from the RV-focused four-chamber view. Markers of RV function included tricuspid annular plane systolic excursion, measured with M-mode imaging of the tricuspid annulus from the RV-focused four-chamber view; fractional area change, as the ratio of the difference between RV end-diastolic and end-systolic areas divided by RV end-diastolic area, from the RV-focused four-chamber view; and DTI-derived peak systolic velocity of the tricuspid annulus.

Speckle-Tracking Echocardiography

By means of a dedicated software package (EchoPAC, version 201, GE Vingmed Ultrasound, Horten, Norway), LV myocardial deformation and LV twist were calculated using manual tracing speckle-tracking analysis (Q analysis), according to current recommendations. Frame rates of >50 frames/sec were used, after optimal sector width and depth adjustments. We calculated peak systolic LV global longitudinal strain (GLS) and global longitudinal strain rate (GLSR) and early diastolic GLSR (GLSRE) as the means of the 17 ventricular segments from the four-chamber, two-chamber, and three-chamber apical views. Additionally, subendocardial and subepicardial myocardial layer deformation was calculated. Peak RV GLS and GLSR were calculated as the means of the six segments (three of the RV free wall and three of the interventricular septum) from the apical four-chamber view. Peak circumferential strain (CircS) and circumferential strain rate (CircSR) were calculated from the six ventricular segments from the short-axis view at the level of the papillary muscles. LV twist was defined as the absolute apex-to-base gradient rotation, expressed in degrees. We measured apical rotation (counterclockwise direction) using the short-axis apical view and basal rotation (clockwise direction) from the short-axis view at the mitral valve level. Attention was focused on obtaining the LV apical cross-section beyond the papillary muscles, with none or the smallest view of the right ventricle, to avoid inaccuracies due to inappropriate selection of the apical plane.

Inter- and intraobserver variability was calculated as the SD of the differences between the first and second measurements and expressed as a percentage of the average value. Values of intra- and interobserver variability were 8% and 10% for LV GLS, 8.3% and 10.2% for LV GLSR, 10.1% and 11.9% for CircS, and 11.1% and 12% for CircSR. Values of intra- and interobserver variability for LV twist were 9% and 11.1%.

3D Echocardiography

Three-dimensional-derived LV volumes and LVEF were calculated using the 4D Auto LVQ tool (EchoPAC) according to previously published methodology. Three-dimensional data sets were acquired, comprising the whole heart in a 90° to 90° pyramidal scan volume and were recorded during breath-hold in passive end-expiration. A multibeat mode over up to four heart cycles was used to achieve high temporal resolution, with a volume rate > 20 frames/sec. After data acquisition, automated orientation of the apical four-chamber, two-chamber, and long-axis planes and endocardial borders was detected for the automatic calculation of LV end-diastolic volume, LV end-systolic volume, and LVEF. Manual correction was performed whenever necessary for optimal orientation and endocardial border delineation. For RV volumetric assessment, full-volume data were acquired from a modified apical RV-focused view from four R wave–gated subvolumes during a single end-expiratory breath-hold according to previously published methodology. The mean volume rate was 23 frames/cardiac cycle (range, 18–28 frames/cardiac cycle). The RV data were digitally exported to a TomTec server (TomTec Imaging Systems, Unterschleissheim, Germany) and analyzed offline using four-dimensional RV-Function version 4.0 (TomTec Imaging Systems). Endocardial border contours were detected from the apical four-chamber, sagittal, and coronal views are both end-diastole and end-systole. RV end-diastolic volume, RV end-systolic volume, and RV ejection fraction (RVEF) were calculated.

Values of intra- and interobserver variability were 7.3% and 9.2% for LVEF and 8.1% and 10% for RVEF.

Statistical Analysis

In our previous studies, the mean absolute change in GLS 30 days after intervention was 4.3 ± 8%, so with α = 0.05 (two-sided) and power of 80%, the required sample size was calculated to be 38 patients, assuming no missing values at 30 days after intervention. Continuous variables were tested for normality using the Kolmogorov-Smirnov test. Normally distributed variables are expressed as mean ± SD. Analysis of variance (general linear model, SPSS version 13; SPSS, Chicago, IL) for repeated measurements was applied for measurements of the examined markers at baseline and at 1, 3, 6, and 12 months after chemotherapy, used as a within-subject factor and to compare the percentage changes in the examined indices between baseline and after chemotherapy (1, 3, 6, and 12 months). Post hoc analysis using Bonferroni correction was used to compare the values of the examined markers between baseline and postchemotherapy time points of follow-up (1, 3, 6, and 12 months) for the effects of chemotherapy regimens (BEAM vs Bu-Thio-Flu), the presence of two or more cardiovascular risk factors (yes vs no), and antihypertensive treatment (yes vs no) with measurements at baseline and during follow-up used as a within-subject factor and the above categorical covariates as a between-subject factors. The F and P values of the interaction between time of measurement of the examined markers and the above categorical covariates were calculated. The F and P values of the comparison between baseline and postchemotherapy time points were calculated. The Greenhouse-Geisser correction was used when the sphericity assumption, as assessed by Mauchly’s test, was not met. Post hoc comparisons were performed with Bonferroni correction.

Effects of Chemotherapy on LVEF

Compared with baseline, LVEF and 3D LVEF were reduced after chemotherapy ( P = .02; Tables 2 and 3 , Figures 1 and 2 ).

Three-dimensionally derived LVEF of a patient before (A) and at 1 month after (B) BMT. LVEF was slightly reduced from 60.5% at baseline (A) to 60.1% at 1 month (B) . CO , Cardiac output; ED , end-diastole; EDV , end-diastolic volume; EF , ejection fraction; ES , end-systole; ESV , end-systolic volume; HR , heart rate; SV , stroke volume.

Three-dimensionally derived LVEF of the same patient as in Figure 1 , at 3 months (A) and 12 months (B) after BMT. LVEF was slightly reduced to 58.2% at 3 months (A) and 58% at 12 months (B) . CO , Cardiac output; ED , end-diastole; EDV , end-diastolic volume; EF , ejection fraction; ES , end-systole; ESV , end-systolic volume; HR , heart rate; SV , stroke volume.

No significant changes in LV diameters and volumes were observed throughout the follow-up period. Fourteen patients (17.5% of the whole study population) had reduced 3D LVEFs (<53%) at the end of the 12-month follow-up period. This was also confirmed 2 weeks after the initial 12-month follow-up study.

Effects of Chemotherapy on Speckle-Tracking Markers of LV Function

Results of speckle-tracking-derived markers are summarized in Table 4 . Compared with baseline, LV GLS values were reduced at 1, 3, 6, and 12 months after BMT ( Figures 3 and 4 ). The reduction in LV GLS was more evident at 3 months after BMT and remained significantly reduced at 6 months and at 12 months (change from baseline: 8% at 1 month, 14% at 3 months, 15% at 6 months, and 15% at 12 months; F = 19.8, P = .001). Myocardial layer deformation analysis indicated that compared with baseline, change in LV GLS at 1 month after BMT was driven mostly by subendocardial longitudinal strain reduction ( P = .02 at 1 month, P = .001 at 3 months, P = .001 at 6 months, and P = .001 at 12 months; change from baseline: 9%, 15%, 15%, and 15%, respectively; F = 18.6, P = .001).

Table 4

Speckle-tracking parameters of function

	Baseline	1 Month	Δ%	3 Months	Δ%	6 Months	Δ%	12 Months	Δ%	F	P
LV GLS	−20 ± 2.2	−18.4 ± 2.1 ∗	8	−17.3 ± 2.2 †	14	−17.1 ± 2.1 ‡	15	−17.1 ± 2.2 §	15	19.8	.001
Subendocardial LV GLS	−22.5 ± 2.4	−20.5 ± 2.3 ∗	9	−19.2 ± 2.3 †	15	−19.2 ± 2.4 ‡	15	−19.1 ± 2.4 §	15	18.6	.001
Subepicardial LV GLS	−17.8 ± 2.1	−16.8 ± 2.2	6	−15.3 ± 2.1 †	14	−15.1 ± 2.2 ‡	15	−15.1 ± 2.1 §	15	15.5	.001
LV GLSR	−1.18 ± 0.2	−1.08 ± 0.2 ∗	8	−1 ± 0.2 †	15	−1 ± 0.2 ‡	15	−0.99 ± 0.2 §	16	14.6	.001
LV GLSRE	−1.32 ± 0.3	−1.18 ± 0.3 ∗	11	−1.04 ± 0.3 †	21	−1.04 ± 0.3 ‡	21	−1.03 ± 0.2 §	22	25.5	.001
CircS	−19.7 ± 3	−19.3 ± 3.1	2	−18.9 ± 3.2	4	−18.8 ± 3.3	5	−18.8 ± 3.2	5	4.7	.10
CircSR	−1.23 ± 0.3	−1.21 ± 0.3	2	−1.19 ± 0.3	4	−1.19 ± 0.2	4	−1.18 ± 0.3	4	3.1	.20
LV twist	14.5 ± 3.5	14.2 ± 3.6	2	13.5 ± 3 †	7	13.4 ± 3.1 ‡	8	13.4 ± 3 §	8	5.1	.03
RV GLS	−22.3 ± 2.6	−20.5 ± 2.6 ∗	8	−20.2 ± 2.4 †	9	−20.1 ± 2.4 ‡	10	−20.1 ± 2.3 §	10	12.8	.02
RV GLSR	−1.32 ± 0.3	−1.25 ± 0.3	5	−1.22 ± 0.2 †	8	−1.22 ± 0.2 ‡	8	−1.22 ± 0.2 §	8	4.4	.04

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