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Left Ventricular Function in Long-Term Survivors of Childhood Lymphoma

The American Journal of Cardiology, 3, 114, pages 483 - 490

Survivors of childhood lymphoma (CL) have markedly increased risk of developing heart failure. Echocardiographic studies after cardiotoxic treatment have primarily demonstrated left ventricular (LV) systolic dysfunction. In the present study, we hypothesized that longer follow-up and a more comprehensive echocardiographic examination would reveal more cardiac abnormalities. We conducted a cross-sectional study with echocardiography 20.4 ± 8.6 years after diagnosis in 125 survivors of CL, grouped according to treatment methods, and compared with matched controls. Treatment included mediastinal radiotherapy (median 40.0 Gy) in 66 and anthracyclines (median dose 160 mg/m2) in 92 survivors of CL. Abnormal LV function, left-sided valve dysfunction, or both occurred in 62 patients (50%). Diastolic dysfunction occurred in 29%. Compared with control subjects, mitral annular early diastolic velocities (e′) were reduced in patients (septal e′ 0.09 ± 0.03 vs 0.12 ± 0.03 m/s, p <0.001), and the E/e′ ratio was increased, particularly after mediastinal radiotherapy (10.6 ± 6.4 vs 5.6 ± 1.3, p <0.001). Survivors of CL had lower fractional shortening than control subjects (32 ± 6 vs 36 ± 7, p <0.001), but mean ejection fraction was equal and overt systolic dysfunction was infrequent. After mediastinal radiotherapy alone, global longitudinal myocardial strain was lower (p <0.05) compared with other treatment groups. Left-sided valvular dysfunction occurred in 55% of patients after mediastinal radiotherapy. In conclusion, survivors of CL had reduced LV diastolic function assessed by tissue Doppler imaging. This was more pronounced after mediastinal radiotherapy, which also frequently led to valvular disease. Systolic function was normal in most survivors of CL.

The aim of the present study was to examine cardiac structure and function in long-term survivors of childhood lymphoma (CL), based on a comprehensive echocardiographic examination. The data were analyzed in relation to cardiotoxic treatment methods and compared with healthy control subjects matched for age, gender, body weight, and blood pressure. We hypothesized that longer follow-up than previous studies would lead to identification of a greater prevalence of cardiac abnormalities and that measuring left ventricular (LV) diastolic function would reveal cardiac dysfunction not disclosed by measures of systolic function or cardiac dimensions.

Methods

The study patients participated in a cross-sectional study including outpatient clinical examination of long-term survivors of CL. 1 The present study assessed cardiac function in the patients, with comparison with a matched control group. Patients were identified from the Cancer Registry of Norway. Patients were eligible if they were diagnosed with either non-Hodgkin lymphoma or Hodgkin lymphoma when aged <18 years, between 1970 and 2000, were aged >18 years at the time of the study, and had survived at least 5 years after diagnosis. Whereas the study comprised survivors of Hodgkin lymphoma from all parts of Norway, survivors of non-Hodgkin lymphoma were included from the south-eastern health region of Norway, which covers approximately 50% of the Norwegian population, because of logistic limitations.

Data on treatment methods and doses were obtained from the patients' medical records. Anthracycline doses were converted to doxorubicin isotoxic doses using a conventional conversion factor of 0.67 × epirubicin dose and 0.833 × daunorubicin dose, respectively. 2 Anthracycline doses are expressed as cumulative dose adjusted for body surface area (m2). Total radiation dose to the mediastinum was registered for each patient. Patients with radiation fields not involving the mediastinum were classified as not receiving radiation to the heart. Patients were categorized into the following 4 treatment groups: (1) “anthracyclines only” (i.e., anthracycline treatment without mediastinal radiotherapy), (2) “mediastinal radiotherapy only” (i.e., radiation fields involving the mediastinum without anthracycline treatment), (3) “anthracyclines and mediastinal radiotherapy in combination,” and (4) “no cardiotoxic treatment” (i.e., neither anthracyclines nor mediastinal irradiation). Analyses were also performed on differences between survivors of CL based on whether they had received mediastinal radiotherapy and anthracyclines. In addition, the effect of different radiation doses on valvular dysfunction was analyzed.

All participants underwent an extensive medical assessment including physical examination, blood sampling, electrocardiography, and a comprehensive echocardiographic examination. Written informed consent was given by all the participants. The study complied with the Declaration of Helsinki and was approved by the Regional Committee for Medical and Health Research Ethics.

A control group for echocardiographic parameters was obtained by matching patients 1:1 for gender, age, body weight, and systolic blood pressure to healthy control subjects selected from a clinical echocardiographic database in the third wave of the Nord-Trøndelag Health Study. This is a cross-sectional study of 50,839 inhabitants (54% of the total) from the mid region of Norway, where a complete echocardiographic examination was performed in 1,296 subjects without known cardiovascular disease, diabetes, or hypertension. 3 Matching 1:1 made it possible to compare different treatment groups with their respective controls, as there were some differences in patient characteristics, for example, age at survey, among the groups of survivors of CL based on treatment.

All echocardiograms were obtained from 2007 to 2009 by experienced sonographers according to a standardized protocol using digital high-end echocardiographic scanners (Vivid 7 or E9; GE Healthcare Vingmed Ultrasound, Horten, Norway). The patients were examined at the Department of Cardiology, Oslo University Hospital, and the results of their examination were reviewed by an experienced cardiologist blinded to the patients' clinical status (SA). The control subjects were examined and reviewed at the Department of Circulation and Medical Imaging, Norwegian University of Science and Technology, Trondheim, by another experienced cardiologist (HD).

LV wall thickness, internal dimension, and fractional shortening (FS) were obtained from M-mode parasternal recordings following convention. 4 LV ejection fraction (EF) and volumes were calculated using Simpson's biplane method. Cardiac output was calculated from LV outflow tract dimension measured in parasternal long-axis view and the integral of the LV outflow tract pulse-wave Doppler signal. To correct for differences in body size, dimensions and cardiac output were indexed to body surface area. Left atrial dimensions were obtained in the patients only, where diameter was measured by M-mode from parasternal long-axis view and biplane area was measured from apical 4-chamber and 2-chamber views. Systolic LV myocardial longitudinal strain measurement (i.e., regional myocardial shortening) was also obtained in the patients, using semiautomatic software from GE (EchoPAC, version 7) from the standard 3 apical imaging planes, using gray-scale cineloop imaging with a frame rate of at least 40 frames/s. Global peak systolic strain was calculated.

Mitral valve inflow was recorded at the tips of the valve. Pulmonary vein inflow was obtained in the upper right pulmonary vein with the sample volume at least 0.5 cm into the vein. From mitral inflow, peak early (E) and late diastolic velocities were recorded, as well as the deceleration time of the E wave. From pulmonary vein inflow, peak systolic, diastolic, and atrial reversed velocities were recorded. The isovolumic relaxation time was derived from simultaneous Doppler recording of the aortic ejection and mitral inflow. Pulse-wave tissue Doppler velocities were recorded from the mitral annular septal and lateral insertions and the peak systolic and early diastolic (e′) tissue velocities obtained over at least 3 cardiac cycles. Ratios of diastolic mitral inflow velocities, pulmonary vein velocities, and E/e′ (using the average of septal and lateral e′) were calculated.

Normal values for LV size and function refer to published recommendations from the American Society of Echocardiography and European Association of Echocardiography.4 and 5 However, we chose to define EF <50% as abnormal, in accordance with clinical practice. 6 We defined systolic dysfunction as EF <50% or FS <27% in female patients and <25% in male patients. We defined diastolic dysfunction as septal e′ <0.08 m/s or lateral e′ <0.10 m/s.

Valvular disease was graded following convention7 and 8: regurgitations and stenoses were graded as mild, moderate, or severe. Minimal regurgitations on left-sided cardiac valves and mild regurgitations on right-sided cardiac valves were considered normal. For patients with previous cardiac valve surgery, the valvular dysfunction before surgery was used for the analyses of valvular disease. In patients with tricuspid regurgitation, peak pressure gradient was measured.

Data with normal distribution are expressed as mean ± SDs, whereas data with skewed distribution are presented as median (twenty-fifth to seventy-fifth percentiles). Student t test, Mann-Whitney test, or 1-way analysis of variance test was used to compare differences between groups, as appropriate. Chi-square test was used to compare categorical variables. A 2-sided p value of <0.05 was considered significant. The least significant difference test was used for post hoc analysis of differences between groups detected by 1-way analysis of variance. Logistic regression analyses were used to evaluate the association between the occurrence of cardiac abnormalities (LV systolic and diastolic dysfunction, left heart valvular dysfunction) and gender, diagnosis, age at diagnosis, age at examination, mediastinal radiotherapy, and anthracycline treatment. Independent variables resulting in p <0.2 were included in multivariate analysis. Statistical analyses were performed with PASW Statistics 18 software from SPSS Inc. (Chicago, Illinois).

Results

In all, 220 survivors of CL were eligible. Of these, 95 patients did not participate: 15 answered questionnaires but did not attend examinations, and 80 did not respond to the invitation. Thus, a total of 125 patients (57%) were included and completed the echocardiographic examination ( Table 1 ). The Regional Committee for Medical and Health Research Ethics did not allow further investigation of nonresponders.

Table 1 Patient characteristics

Variable All Patients Anthracyclines Only Mediastinal Radiotherapy Only Anthracyclines and Mediastinal Radiotherapy No Cardiotoxic Treatment
Number of patients 125 50 (40%) 23 (18%) 43 (34%) 9 (7%)
Age at diagnosis (years) 14.0 (10.5, 16.4) 12.1 (8.0, 14.6) 14.1 (11.6, 16.8) 15.3 (14.0, 16.5) 12.2 (7.9, 15.3)
Age at exam (years) 33.0 (26.8, 39.6) 29.2 (23.4, 36.1) 42.9 (38.7, 47.7) 29.1 (26.7, 35.9) 39.9 (37.9, 46.0)
Follow-up time (years) 20.4 ± 8.6 18.2 ± 7.1 29.3 ± 6.5 16.3 ± 6.9 29.7 ± 5.4
Systolic blood pressure (mm Hg) 128 ± 15 129 ± 17 130 ± 16 125 ± 12 142 ± 9
Body weight (kg) 74 ± 14 74 ± 12 77 ± 13 71 ± 14 81 ± 21
Body surface area (m2) 1.87 ± 0.20 1.89 ± 0.17 1.92 ± 0.19 1.80 ± 0.19 1.94 ± 0.28
Hodgkin 81 (65%) 17 (34%) 23 (100%) 35 (81%) 6 (67%)
Non-Hodgkin 44 (35%) 33 (66%) 0 8 (19%) 3 (33%)
Female 58 (46%) 18 (36%) 7 (30%) 29 (67%) 4 (44%)
Treatment with anthracyclines 93 (74%) 50 (100%) 0 43 (100%) 0
Doxorubicin 84 (67%) 47 (94%) 0 37 (86%) 0
Epirubicin 9 (7%) 1 (2%) 0 8 (19%) 0
Daunorubicin 5 (4%) 3 (6%) 0 2 (5%) 0
Doxorubicin isotoxic dose (mg/m2) 160 (102, 214) 155 (120, 210) 160 (100, 215)
Radiotherapy to the mediastinum 66 (53%) 0 23 (100%) 43 (100%) 0
Radiation dose (Gray) 40 (25, 40) 40 (40, 40) 35 (20, 40)
Alkylating cytostatics 100 (80%) 46 (92%) 12 (52%) 37 (86%) 5 (56%)

Data are presented as mean ± standard deviation, median (interquartile range), or frequencies (percentage).

Patient characteristics and treatment methods are listed in Table 1 . Patients and control subjects were well matched, with no differences in median age (33 vs 33 years, p = 0.928), mean systolic blood pressure (128 vs 128 mm Hg, p = 0.754), body weight (74 vs 75 kg, p = 0.810) or body surface area (1.87 vs 1.89 m2, p = 0.581).

Occurrence of LV systolic dysfunction did not differ between patients and control subjects, but diastolic dysfunction occurred 7 times more frequently in patients ( Table 2 ). No associations emerged between patient characteristics or treatment, respectively, and the occurrence of LV systolic dysfunction in regression analyses. Univariate analysis showed a borderline significant association between mediastinal radiotherapy and diastolic dysfunction (odds ratio 2.2, 95% confidence interval 1.0 to 5.0, p = 0.05). In multivariate analysis, however, only age at examination was independently associated with diastolic dysfunction (odds ratio 1.1, 95% confidence interval 1.0 to 1.2, p = 0.001). In multivariate analysis, mediastinal radiotherapy (odds ratio 27.8, 95% confidence interval 6.6 to 118, p <0.001) was independently associated with the prevalence of left-sided valvular dysfunction, in addition to age at examination (odds ratio 1.2, 95% confidence interval 1.1 to 1.3, p = 0.001).

Table 2 Prevalence of cardiac abnormalities

Variable Number of Patients (%) Number of Controls (%) p Value
LV ejection fraction <50% 5 (4%) 12 (10%) 0.138
LV fractional shortening <27% in females, <25% in males 10 (8%) 4 (3%) 0.096
LV systolic dysfunction 12 (10%) 16 (13%) 0.422
LV diastolic dysfunction 36 (29%) 5 (4%) <0.001
Mitral inflow peak early velocity to average e′ ratio (E/e′) ≥13 13 (10%) 0 <0.001
LV systolic and/or diastolic dysfunction 40 (32%) 19 (15%) 0.002
Left-sided cardiac valve dysfunction 39 (31%)  
LV and/or left-sided valve dysfunction 62 (50%)  
Abnormal LV diameter, indexed to body surface area 15 (12%) 10 (8%) 0.312

Low ejection fraction and/or low fractional shortening.

Low early diastolic peak mitral annular velocity (e′): septal <0.08 m/s and/or lateral <0.10 m/s.

LV = left ventricular.

The patients had lower FS than control subjects, except for the no cardiotoxic treatment group ( Table 3 ). Cardiac index was also lower, despite a slightly higher heart rate in patients compared with control subjects (69 ± 12 vs 66 ± 10 beats/min, p = 0.010). EF was not different among treatment groups or between patients and control subjects. Patients treated with mediastinal radiation only had a trend toward lower global strain than the other 3 treatment groups. Comparable strain values were not available in the control group. There was a highly significant, yet small, difference in septal peak systolic mitral annular velocities between patients and controls, whereas lateral systolic velocities were not significantly different.

Table 3 Left ventricular dimensions and systolic function in patients, controls, and different treatment groups

Variable Patients (n = 125) Controls (n = 125) p Anthracyclines Only (n = 50) Mediastinal Radiotherapy Only (n = 23) Anthracyclines and Radiotherapy (n = 43) No Cardiotoxic Treatment (n = 9) p
Indexed interventricular septum dimension (cm/m2) 0.45 ± 0.06 0.43 ± 0.07 0.003 0.45 ± 0.06 0.48 ± 0.07 0.45 ± 0.05 0.46 ± 0.06 0.237
Indexed internal dimension (cm/m2) 2.64 ± 0.24 2.70 ± 0.49 0.069 2.72 ± 0.19 2.49 ± 0.25 2.64 ± 0.26 2.64 ± 0.33 0.002
Indexed posterior wall dimension (cm/m2) 0.43 ± 0.05 0.45 ± 0.07 0.012 0.43 ± 0.05 0.43 ± 0.05 0.43 ± 0.05 0.46 ± 0.03 0.406
Indexed end diastolic volume (ml/m2) 50 ± 9 51 ± 10 0.166 52 ± 9 46 ± 12 48 ± 9 49 ± 5 0.091
Fractional shortening (%) 32 ± 6 36 ± 7 <0.001 32 ± 5 32 ± 8 31 ± 5 37 ± 4 0.054
Ejection fraction (%) 56 ± 6 57 ± 7 0.167 56 ± 6 55 ± 8 56 ± 5 60 ± 3 0.225
Cardiac index (L/min/m2) 2.42 ± 0.49 2.62 ± 0.61 0.004 2.38 ± 0.50 2.55 ± 0.60 2.41 ± 0.46 2.37 ± 0.23 0.593
Global strain (%) −18.5 ± 2.3 −18.7 ± 1.9 −17.2 ± 3.3 −18.7 ± 2.1 −19.1 ± 2.6 0.057
Septal peak systolic mitral annular velocity (m/s) 0.07 ± 0.02 0.08 ± 0.01 <0.001 0.07 ± 0.01 0.06 ± 0.01 0.07 ± 0.01 0.08 ± 0.03 0.030
Lateral peak systolic mitral annular velocity (m/s) 0.09 ± 0.02 0.10 ± 0.02 0.100 0.09 ± 0.02 0.08 ± 0.01 0.10 ± 0.03 0.09 ± 0.03 0.042

For differences between patients and controls (t test).

For differences between treatment groups (ANOVA).

Significantly different from all other treatment groups in post hoc analysis (p <0.05).

The patients had reduced diastolic function, as shown by lower e′ and higher E/e′ ratio, than control subjects ( Table 4 ). However, the 9 patients with no cardiotoxic treatment did not differ in lateral e′ and E/e′ compared with control subjects ( Table 5 ). Patients treated with mediastinal radiotherapy only had lower e′, higher E/e′, and higher peak tricuspid valve regurgitation pressure gradient than the other patients ( Table 4 ). After exclusion of patients with left-sided valvular dysfunction from the analyses, there were still highly significant differences in e′ and E/e′ ratio between patients and controls (all comparisons p ≤0.001). The left atrial area was equal in the different patient groups but was not measured in controls ( Table 4 ). Patients treated with mediastinal radiotherapy had lower indexed LV internal dimension than control subjects ( Table 5 ). There were no systematic differences in LV wall thickness.

Table 4 Left ventricular diastolic function in patients, controls, and different treatment groups

Variable Patients (n = 125) Controls (n = 125) p Anthracyclines Only (n = 50) Mediastinal Radiotherapy Only (n = 23) Anthracyclines and Radiotherapy (n = 43) No Cardiotoxic Treatment (n = 9) p
Mitral inflow peak early (E) velocity (m/s) 0.87 ± 0.29 0.78 ± 0.16 0.001 0.81 ± 0.14 1.10 ± 0.37 0.85 ± 0.34 0.78 ± 0.20 0.001
Mitral inflow E wave deceleration time (ms) 183 ± 47 200 ± 53 0.007 181 ± 44 182 ± 56 181 ± 45 205 ± 49 0.527
Mitral inflow peak late (A) velocity (m/s) 0.60 ± 0.26 0.48 ± 0.16 <0.001 0.46 ± 0.12 0.90 ± 0.34 0.59 ± 0.22 0.62 ± 0.13 <0.001
Mitral inflow E/A ratio 1.60 ± 0.57 1.80 ± 0.80 0.023 1.86 ± 0.56 1.25 ± 0.40 1.53 ± 0.55 1.29 ± 0.44 <0.001
Pulmonary vein systolic to diastolic wave ratio 0.91 ± 0.32 1.09 ± 0.36 <0.001 0.84 ± 0.27 0.87 ± 0.29 0.94 ± 0.36 1.25 ± 0.32 0.009
Isovolumic relaxation time (ms) 89 ± 18 90 ± 18 0.729 91 ± 17 76 ± 19 88 ± 19 95 ± 15 0.191
Tricuspid regurgitation pressure gradient (mm Hg) 20 ± 6 18 ± 5 25 ± 7 19 ± 5 18 ± 4 <0.001
Early diastolic annular velocity (e′) septal (m/s) 0.09 ± 0.03 0.12 ± 0.03 <0.001 0.10 ± 0.03 0.07 ± 0.02 0.10 ± 0.03 0.09 ± 0.02 <0.001
Early diastolic annular velocity (e′) lateral (m/s) 0.14 ± 0.04 0.16 ± 0.04 <0.001 0.15 ± 0.04 0.10 ± 0.02 0.14 ± 0.03 0.13 ± 0.02 <0.001
Mitral inflow E to average e′ ratio (E/e′) 8.6 ± 5.0 5.6 ± 1.4 <0.001 6.8 ± 1.8 14.5 ± 6.4 8.2 ± 5.1 7.2 ± 2.5 <0.001
Left atrial area (cm2) 15.8 ± 3.3 15.8 ± 3.4 16.2 ± 3.1 15.3 ± 3.2 16.8 ± 3.5 0.631

For differences between patients and controls (t test).

For differences between treatment groups (ANOVA).

Significantly different from all other treatment groups in post hoc analysis (p <0.05).

Table 5 Selected measures of left ventricular dimension and function in patients versus matched controls according to treatment groups

Variable Patient Group Controls p Value
  Anthracyclines Only (n = 50) Controls

(n = 50)
 
Indexed internal dimension (cm/m2) 2.72 ± 0.19 2.67 ± 0.27 0.260
Fractional shortening (%) 32 ± 5 36 ± 7 0.001
Early diastolic annular velocity (e′) septal (m/s) 0.10 ± 0.03 0.13 ± 0.03 <0.001
Early diastolic annular velocity (e′) lateral (m/s) 0.15 ± 0.04 0.17 ± 0.04 0.003
Mitral inflow peak early velocity to average e′ ratio (E/e′) 6.8 ± 1.8 5.6 ± 1.4 <0.001
Age at exam (years) 30 ± 7 32 ± 9 0.182
  Mediastinal radiotherapy only (n = 23) Controls

(n = 23)
 
Indexed internal dimension (cm/m2) 2.49 ± 0.25 2.63 ± 0.29 0.071
Fractional shortening (%) 32 ± 8 35 ± 8 0.220
Early diastolic annular velocity (e′) septal (m/s) 0.07 ± 0.02 0.11 ± 0.02 <0.001
Early diastolic annular velocity (e′) lateral (m/s) 0.10 ± 0.02 0.14 ± 0.04 <0.001
Mitral inflow peak early velocity to average e′ ratio (E/e′) 14.5 ± 6.4 5.6 ± 1.1 <0.001
Age at exam (years) 43 ± 7 36 ± 9 0.004
  Anthracyclines and radiotherapy (n = 43) Controls

(n = 43)
 
Indexed internal dimension (cm/m2) 2.64 ± 0.26 2.79 ± 0.25 0.006
Fractional shortening (%) 31 ± 5 35 ± 5 0.003
Early diastolic annular velocity (e′) septal (m/s) 0.10 ± 0.03 0.13 ± 0.03 <0.001
Early diastolic annular velocity (e′) lateral (m/s) 0.14 ± 0.03 0.16 ± 0.03 0.014
Mitral inflow peak early velocity to average e′ ratio (E/e′) 8.2 ± 5.2 5.6 ± 1.4 0.002
Age at exam (years) 31 ± 7 35 ± 9 0.026
  All mediastinal radiotherapy

(n = 66)
Controls

(n = 66)
 
Indexed internal dimension (cm/m2) 2.58 ± 0.26 2.73 ± 0.27 0.002
Fractional shortening (%) 32 ± 6 35 ± 6 0.003
Early diastolic annular velocity (e′) septal (m/s) 0.09 ± 0.03 0.12 ± 0.03 <0.001
Early diastolic annular velocity (e′) lateral (m/s) 0.12 ± 0.04 0.15 ± 0.03 <0.001
Mitral inflow peak early velocity to average e′ ratio (E/e′) 10.6 ± 6.4 5.6 ± 1.3 <0.001
Age at exam (years) 35 ± 9 35 ± 9 0.983
  No cardiotoxic treatment (n = 9) Controls

(n = 9)
 
Indexed internal dimension (cm/m2) 2.64 ± 0.33 2.66 ± 0.23 0.938
Fractional shortening (%) 37 ± 4 39 ± 7 0.544
Early diastolic annular velocity (e′) septal (m/s) 0.09 ± 0.02 0.12 ± 0.03 0.024
Early diastolic annular velocity (e′) lateral (m/s) 0.13 ± 0.02 0.13 ± 0.03 0.890
Mitral inflow peak early velocity to average e′ ratio (E/e′) 7.2 ± 2.5 6.3 ± 1.4 0.436
Age at exam (years) 41 ± 4 31 ± 10 0.014

In patients treated with mediastinal radiotherapy, 27 (41%) had aortic valve dysfunction and 26 (39%) had mitral valve dysfunction ( Figure 1 ). Several of the patients had combined stenosis and regurgitation. Three patients had undergone previous surgery on left-sided cardiac valves. Of these, 2 had combined aortic and mitral valve replacement, whereas 1 had aortic valve replacement only. Patients not treated with mediastinal radiotherapy generally had preserved valvular function. Mild mitral regurgitation was present in 3 patients (5%). Mediastinal radiotherapy was significantly associated with the occurrence of aortic stenosis (p = 0.003), aortic regurgitation (p <0.001), and mitral regurgitation (p <0.001) but not with mitral stenosis (p = 0.154), which occurred infrequently.

gr1

Figure 1 (A) Prevalence of left-sided valvular dysfunction in the 66 patients treated with mediastinal radiotherapy. Bars indicate no, mild, moderate, and severe valvular dysfunction, respectively. (B) Prevalence of aortic and mitral valve disease in patients treated with mediastinal radiotherapy, grouped after radiation dose in Gray. Dark bars indicate that valvular disease is present, white bars that valvular disease is absent.

Figure 1 shows valve dysfunction according to radiation dose categorized into 3 groups. Increasing radiation doses were associated with a greater prevalence of aortic valve dysfunction (p <0.001). A trend toward more mitral valve dysfunction with higher radiation dose was not statistically significant (p = 0.135).

Pulmonary and tricuspid regurgitation were more frequent in patients treated with mediastinal radiotherapy compared with the other patients (p = 0.003 and p = 0.001 for the difference, respectively). However, excluding minimal and mild regurgitations left only 2 patients (2%) with pulmonary regurgitation and 9 patients (7%) with tricuspid regurgitation in the entire group of patients. None had severe or surgically corrected right-sided cardiac valve disease.

Discussion

In this study of 125 survivors of CL, a mean of 20 years after diagnosis, we found only a small impairment of LV systolic function compared with matched healthy control subjects. In contrast, LV diastolic function was significantly impaired in survivors. Valvular dysfunction occurred in about 1 in 3 patients but almost exclusively in those treated with mediastinal radiotherapy.

Anthracycline treatment has been associated with progressive LV thinning and dilation over time, in survivors of both childhood leukemia9, 10, and 11 and adult lymphoma. 12 Given this, and the long follow-up time in our study, we expected to find a clear difference in LV dimensions in patients versus control subjects. However, we did not identify any difference in LV dimensions after anthracycline treatment. We believe the likely reason for this is that cumulative anthracycline doses used in our patients are lower compared with most previous studies. In contrast, there was a significant decrease in LV internal dimension in survivors of CL treated with mediastinal radiotherapy. This has been shown previously. 13 A plausible explanation for this is that radiotherapy induces fibrosis in the growing heart. 14

Survivors of CL or childhood leukemia face up to a 15-fold increased risk for congestive heart failure. 15 Increased risk is seen after both anthracycline treatment and radiotherapy, 16 and the greatest prevalence of symptomatic cardiac events is seen after combined treatment. 17 Anthracyclines cause decreased LV systolic function9 and 11 and late-onset heart failure.15 and 18 Despite all this, we observed only small differences in systolic function in our patients treated with cardiotoxic methods. Mean FS was lower but still well within reference values, 4 whereas mean EF was not significantly different, and overt systolic dysfunction was infrequent. Peak global myocardial strain is presumed to be a more sensitive marker of systolic dysfunction 19 and was lower in the group that had been treated with mediastinal radiotherapy only compared with other patient groups, indicating that radiotherapy leads to a more pronounced reduction in systolic function.

In contrast to the seemingly mild impairment of LV systolic function in the patients in our study, diastolic dysfunction occurred in almost 1 of 3, and all but one of the parameters of diastolic function were different between patients and control subjects. We defined diastolic dysfunction by a practical approach with assessment of e′, as recommended by the American Society of Echocardiography. 5 In clinical practice, integrated evaluation of a range of diastolic measures is recommended. In contrast to the biphasic patterns of mitral inflow peak early to late diastolic velocity ratio, deceleration time, and isovolumic relaxation time, however, e′ decreases gradually with progressive worsening of diastolic function. This makes interpretation of the results, in particular mean values for a group, easier. We observed only a small difference in peak systolic mitral annular velocity between patients and control subjects, indicating that the observed differences in e′ are not just a result of reduced longitudinal function of the heart.

Several recent studies have failed to show impaired diastolic function associated with anthracycline therapy with low doses in childhood.20, 21, 22, and 23 In our study, the observed reduction in diastolic function after a median dose of 160 mg/m2 (doxorubicin isotoxic dose) is highly significant. Another study showed reduced septal e′ in survivors of childhood Hodgkin lymphoma compared with control subjects but no difference between patients treated with and those not treated with mediastinal radiotherapy. 24 In our study, there is a striking decrease in e′ and increase in E/e′ after mediastinal radiotherapy compared with the other patients. Both larger patient and control groups and longer follow-up time in our study can possibly explain the discrepant findings.

With normal EF, average E/e′ ≥13 indicates increased filling pressures, implying more advanced diastolic dysfunction. 5 In the patients treated with mediastinal radiotherapy only, the mean value for E/e′ was above this threshold. Still, the left atrial size was not different from the other patient groups. Increased filling pressures over time lead to left atrial enlargement. A possible explanation for why we did not observe any differences in left atrial size is the smaller size of irradiated hearts as reflected by the lower LV internal dimension in the patients treated with mediastinal radiotherapy.

Age at examination being the only independent predictor of diastolic dysfunction in multivariate analysis of our data can be explained by the large influence increasing age has on diastolic function in general. However, diastolic dysfunction occurs prematurely in these patient groups, as demonstrated by lack of diastolic dysfunction in our age-matched controls. Indeed, an important strength in our study is the use of a control group larger and matched for more clinical parameters than the control groups in comparable studies.20, 21, 22, 23, and 24 Comparison with closely matched controls allows us to disclose harmful late effects on LV diastolic function after both anthracycline treatment and mediastinal radiotherapy.

LV diastolic dysfunction has been shown to be a strong and independent predictor of all-cause mortality in a general population. 25 Heidenreich et al 26 showed that survivors of adult Hodgkin lymphoma with signs of diastolic dysfunction after mediastinal radiotherapy had reduced cardiac event-free survival. Therefore, there is reason to suspect that survivors of CL with LV diastolic dysfunction face a higher risk of cardiac events.

Published guidelines recommend cardiac screening with echocardiography or multiple gated acquisition scan after anthracycline treatment in childhood. 27 We discourage the use of multiple gated acquisition scan, as it only gives information on systolic function and exposes the patient to ionizing radiation.

The high risk of cardiac valve dysfunction after radiation to the heart is known. 13 In our study, left-sided valve dysfunction was present in as many as 55% of the patients treated with mediastinal radiotherapy, and the risk was dose dependent, in accordance with previous studies. 28 In patients not exposed to mediastinal radiotherapy, there was no left-sided valve disease except for 3 patients with only mild mitral regurgitation, indicating that anthracyclines in the doses given lead to no or minimal risk for developing valve disease.

Our study has some limitations. Most importantly, different reviewers of the echocardiograms in patients and control subjects leave the possibility of systematic error. However, patients and control subjects were examined using the same type of machines, according to the same standards, and e′ is a highly reproducible parameter. 5 We believe the consistency in our data, with corresponding differences in all diastolic parameters between patients and control subjects, and between patients exposed to cardiotoxic treatment and not, strongly indicates that the observed differences in diastolic function are not due to bias. Furthermore, by randomly selecting matched controls from a large independent sample, we avoided the possible selection bias that might exist in other control samples. A somewhat greater prevalence of systolic dysfunction in controls than expected, mostly because of EF just below 50%, could be due to chance and could explain why systolic dysfunction was not overrepresented in the patients. Echocardiographic data early after treatment were not available. Thus, we cannot know whether patients with cardiac abnormalities also were affected early after cardiotoxic treatment. In addition, we do not have systematic data on cardiac symptoms in our patients. Our study was a cross-sectional study of survivors. We could not assess possible cardiac deaths in survivors before study recruitment. Echocardiographic data are surrogate markers for clinical events. Still, LV dysfunction has been shown to be a strong predictor of morbidity and mortality.6, 25, and 26 Moreover, radiation-induced valvular dysfunction will eventually progress to severe and symptomatic valve disease in many patients. Data on the 94 survivors of CL (43%) who did not participate in the study are lacking. If there is a skewed distribution of cardiac abnormalities, extrapolation of our data to a general population of survivors of CL could be problematic. However, clear differences in terms of treatment methods in our study would be expected to reflect true differences in the entire patient group.

Disclosures

The authors have no conflicts of interest to disclose.

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Footnotes

a Department of Cardiology, Oslo University Hospital, Rikshospitalet, Oslo, Norway

b Department of Internal Medicine, Elverum, Innlandet Hospital Trust, Elverum, Norway

c National Resource Centre for Late Effects after Cancer Treatment, Oslo University Hospital, Radiumhospitalet, Oslo, Norway

d Department of Medicine, Levanger Hospital, Nord-Trøndelag Health Trust, Levanger, Norway

e Department of Circulation and Medical Imaging, Norwegian University of Science and Technology, Trondheim, Norway

Corresponding author: Tel: (+47) 99517155; fax: (+47) 62438575.

The study has been supported in part by Helse Sør-Øst Regional Health Trust (Hamar, Norway).

See page 489 for disclosure information.