Background
Current 5-year survival rates for pediatric malignancies in developed nations have increased from 58% in 1975–1977 to 83% for those diagnosed between 2005 and 2011 [
1]. However, these dramatic improvements in cancer-related survival have accentuated the long-term consequences of cancer treatment, with survivors of pediatric malignancies experiencing increased morbidity and early mortality due to treatment-related chronic health conditions [
2‐
4]. Cardiovascular disease is the most common morbidity experienced by pediatric cancer survivors with 11% of survivors having a diagnosable cardiac condition prior to 40 years of age, of which heart failure is the predominant cause [
5]. This has led to a shift in focus, whereby treatment success is determined by the balance between treatment efficacy and the risk of treatment-related toxicities [
6]. However, despite international recommendations, less than 28% of survivors are receiving appropriate cardiac screening [
7].
The current paradigm for preventing cardiotoxicity relies on the early detection of cardiac dysfunction when it may be more amenable to initiation of heart failure therapy [
8]. Clinical decision making is based on serial changes in resting left ventricular (LV) ejection fraction (LVEF) or LV fractional shortening (FS), which is assessed using two-dimensional (2D) echocardiography or radionucleotide ventriculography [
8]. The identification of LVEF or LV FS below the lower limit of normal should prompt the initiation of cardioprotective heart failure therapies [
6,
8]. For those patients who are undergoing active treatment, this may also result in treatment modification, delay or cessation [
6]. However, clinical decision making is complicated by the lack of sensitivity of LVEF and LV FS in explaining treatment-induced functional limitations, patients’ symptoms and longer-term heart failure events [
9,
10]. This has resulted in increased interest in alternative surveillance methods for identifying cardiac dysfunction and quantifying heart failure risk [
8]. The assessment of myocardial deformation via novel resting echocardiographic or cardiovascular magnetic resonance (CMR) methods are emerging as more sensitive markers of sub-clinical cardiac dysfunction in various cancer groups. However, the degree to which these measures are associated with functional impairment and quantifiable heart failure symptoms such as exercise intolerance is unclear.
Exercise intolerance, defined as reduced cardiopulmonary fitness or peak oxygen consumption (peak VO
2) measured from a cardiopulmonary exercise test (CPET), has proven clinical utility in quantifying heart failure symptoms and predicting prognosis [
11,
12]. Recent advances in cardiac imaging have enabled the measurement of cardiac function augmentation with exercise (termed “cardiac reserve”) to be assessed with greater accuracy and have been shown to be strongly associated with peak oxygen consumption (VO
2 ) [
13]. Thus, both peak VO
2 and cardiac reserve may provide greater sensitivity for detecting sub-clinical cardiac dysfunction than resting measures [
12]. However, associations between exercise intolerance and cardiac function (including cardiac reserve) in pediatric cancer survivors remain inconclusive [
14,
15].
Therefore, the aim of this study was to explore the presence of exercise intolerance in survivors of childhood and adolescent malignancy at high risk of cardiac dysfunction, and to explore its relationship with measures of resting cardiac function, and exercise-based measures of cardiac haemodynamics and systolic function.
Methods
Participant population and study design
Participants were cancer survivors treated or undergoing active treatment for pediatric haematologic malignancy at the Royal Children’s Hospital, Monash Medical Centre or Alfred Hospital, Melbourne. Participation involved recruitment from attendance at routine outpatient clinics, with participants providing informed written consent prior to participation in the study. This study was approved by the ethics committee of the Melbourne Royal Children’s Hospital (HREC 35102D) and the Alfred Hospital (HREC 00315) and was conducted in accordance with the Declaration of Helsinki guidelines.
Enrollment criteria included: (1) previous treatment with anthracycline chemotherapy with or without craniospinal or chest-targeted radiotherapy, and (2) height > 120 cm (in order to reach pedals for exercise testing). Participants were excluded if they had a previous history of severe symptomatic cardiac disease or had a contraindication to CMR.
Outcome measures
Comprehensive resting and exercise evaluation was completed at the Baker Heart and Diabetes Institute, Melbourne. Participants were evaluated with i) comprehensive resting transthoracic echocardiogram to assess LVEF, LV FS and global longitudinal strain (GLS), ii) a maximal CPET to evaluate peak VO2 as an indication of cardiopulmonary fitness, and iii) resting and exercise CMR (exCMR) to determine resting GLS, and resting and peak exercise LVEF, right ventricular (RV) ejection fraction (RVEF), stroke volume index (SVI), heart rate and cardiac index (CI) as measures of cardiac reserve. Participants were classified by normal peak VO2 or impaired peak VO2 defined as peak VO2 ≥ 85% age-predicted values. Cardiovascular risk factors were assessed at the time of study enrollment. Participants were assessed for hypertension, diabetes mellitus, chronic renal insufficiency and body mass index (BMI). Haemoglobin concentration was obtained from routine clinical blood results conducted within 2 months of the study visit, and participants were also screened for pulmonary comorbidities that could provide an alternative explanation for exertional intolerance.
Exercise capacity
CPET was conducted on an electronically braked cycle ergometer (Lode Excalibur, Groningen, The Netherlands) for the measurement of peak VO
2. Workload was increased using a ramp protocol which began at 10–25 watts (W) and progressively increased at 10–30 W/min until volitional exhaustion. Respiratory gas analysis was measured continuously throughout the test using a calibrated metabolic cart (True One 2400, Parvomedics, Salt Lake City, Utah, USA). Heart rate, rhythm and presence of ischemia was measured continuously by 12-lead electrocardiogram (ECG) (Norav Medical, Wiesbaden, Germany). Peak V̇O
2 was defined as a 30-s rolling average of the six highest 5-s oxygen uptake values. Participants were classified as having impaired peak VO
2 if they achieved < 85% of predicted values for children/adolescents [
16] or adults [
17] in line with American Thoracic Society guidelines for CPET interpretation [
18]. The anaerobic threshold was calculated using the V-slope method [
19], with the VO
2 at the anaerobic threshold expressed as an absolute value and as a proportion of each participant’s predicted peak VO
2.
Echocardiography
Resting cardiac function was assessed from a comprehensive resting echocardiogram (Vivid E95, General Electric Healthcare, Milwaukee, Wisconsin, USA), with images saved in a digital format for offline analysis (Echopac v13.0.00, General Electric Healthcare). A full-volume three-dimensional data set was acquired. LV end-diastolic and end-systolic volumes were measured according to standard recommendations [
20]. Two-dimensional GLS was quantified from three apical views at a temporal resolution of 60–90 frame/s. The average negative value on the strain curve was reported as GLS. Doppler measures of diastolic function were acquired and analyzed per guideline recommendations [
21].
CMR imaging
CMR imaging was performed with a 3 T CMR system (MAGNETOM Prisma, Siemens Healthineers, Erlangen, Germany) with a 5-element phased array coil. Ungated real-time balanced steady state free-precision cine imaging was performed with a parallel imaging acceleration factor of 3 and subsequent GRAPPA reconstruction without cardiac or respiratory gating. Forty (during exercise) or 100 (at rest) consecutive frames were acquired with a temporal resolution of 39 ± 3 msec in a short- and long-axis plane. Typical imaging parameters were field of view = 360 mm, 128 × 128 matrix, voxel size = 2.8 × 2.8 × 8 mm, slice gap = 0 mm, echo time = 1.18 ms, echo spacing = 2.6 ms, flip angle = 48°-68°, bandwidth = 1260 Hz/Px .
Statistical analysis
Data analyses were conducted using SPSS statistical software (version 24, Statistical Package for the Social Sciences, International Business Machines, Inc., Armonk, New York, USA). The distribution of continuous variables was tested using a Kolmogorov-Smirnov test. Categorical variables are expressed as n (%), whilst continuous variables are expressed as mean ± standard deviation or median (interquartile range) as appropriate. Differences in participant characteristics were compared by independent t-tests or Mann-Whitney U tests for continuous variables, and chi-square or fisher’s exact tests for categorical variables. Differences in the exCMR cardiac response to exercise was assessed using repeated measures ANOVA (with an interaction term for group x exercise response), with post-hoc analysis conducted using Bonferroni correction. Pearson correlations were used to test for associations between peak VO2 and measures of cardiac function and peripheral muscle oxygen extraction. A 2-sided P value of < 0.05 was considered statistically significant.
Discussion
The main finding from this study was that the classification of pediatric cancer survivors into normal or reduced cardiopulmonary fitness identifies two distinct phenotypes. Specifically, those with normal fitness have a significant augmentation of CI, which occurs due to a significant increase in both heart rate and SVI. In contrast, survivors with impaired fitness have a blunted increase in CI that is primarily driven by increases in heart rate and minimal change in SVI. These differences in fitness and exercise cardiac reserve exist despite no significant differences between groups in measures of cardiac function currently used to quantify heart failure risk and guide clinical decision making.
There is growing awareness of the limitations for the current approach of cardiotoxicity screening in pediatric cancer survivors [
6,
8]. Current guidelines are centered on detecting > 10% reductions in resting fractional shortening or LVEF [
6,
8], however there is little evidence to show that this approach reliably predicts subsequent cardiovascular morbidity and mortality [
6]. Furthermore, reductions in these measures that remain within the normal range show little correlation with exercise capacity or quality of life [
23]. We have investigated an alternative approach that focuses on peak VO
2, a holistic measure of cardiovascular reserve that has been shown to correlate with heart failure incidence [
24,
25], prognosis [
26,
27] and quality of life [
28] among healthy and clinical cohorts. On average, our cohort had a peak VO
2 that was 19% below predicted values for age, gender and height. This is consistent with a number of other studies documenting pediatric cancer survivors previously treated with anthracyclines and/or chest radiation having a peak VO
2 that is 8–20% below predicted values or matched control subjects [
14,
29,
30]. However, by dividing the spectrum of exercise responses into a binary construct, we have identified a group with marked exercise impairment who have demonstrable abnormalities in cardiac function inducible during exercise stress. The reduction in exercise capacity and cardiac function is likely to be a persistent effect of treatment, as cross-sectional studies have reported that between 30 and 79% of long-term survivors measured > 5 years post-treatment have impaired peak VO
2 [
30‐
32]. Notably, evidence from large prospective studies in non-cancer populations has shown that incident heart failure risk increased by 16% for each 3.5 mL/kg/min decrement in peak VO
2 [
24,
25]. Given the average peak VO
2 for the impaired fitness group was 12.1 mL/kg/min below predicted, we would infer this group is at substantially greater risk of development of heart failure symptoms over time than the normal fitness group, who on average, achieved almost 100% of predicted peak VO
2. This ensues despite no significant differences between our two study groups in resting echocardiographic measures of LV FS and LVEF, nor even in more novel echocardiographic and CMR-derived measures of GLS. This highlights that the current standard of care approach to quantifying cardiac function is insensitive to clinically important differences in peak VO
2 and heart failure risk.
Given that heart failure is typified by an inability of cardiac function to meet metabolic demand, we hypothesized that assessing cardiac function during periods of increased metabolic demand (such as exercise) should be more sensitive to heart failure risk than the assessment of cardiac function at rest when metabolic demands are low. The inclusion of novel exercise cardiac imaging has allowed us to demonstrate cardiac reserve is significantly reduced in pediatric cancer survivors with reduced peak VO
2. Specifically, we found that survivors with reduced peak VO
2 showed a blunted increase in LVEF and minimal augmentation of SVI during exercise, resulting in a blunted increase in exercise CI such that peak exercise CI was 24% lower than survivors with normal fitness. Two cross-sectional reports in pediatric cancer survivors have reported similar results, with survivors demonstrating lower exercise SVI and CI than age- and gender-matched controls [
33,
34]. However, our study is the first in pediatric cancer survivors to document this relationship with impaired peak VO
2. A handful of cross-sectional studies have investigated cardiac impairment in long-term pediatric cancer survivors with normal or reduced peak VO
2 [
29,
30,
35]. However results from these studies have been inconsistent, which may relate to the assessment of cardiac function in the resting state. This is supported by findings from our study, in which there was no significant difference in resting LV FS, LVEF or GLS between our two study groups, nor did these measures correlate with peak VO
2. The largest of these previous studies [
35] demonstrated that impaired peak VO
2 was associated with reduced resting GLS, but not resting LVEF in 1041 long-term (> 10 years) pediatric cancer survivors, supporting the notion that exercise intolerance is a maker of cardiac dysfunction in cancer survivors. However, results from our study suggest that impairments in fitness and cardiac reserve may precede impairment in GLS. The fact that RVEF was paradoxically lower at rest in fitter survivors is consistent with work in athletic populations in which lower resting RVEF is associated with greater fitness [
36]. In the current population, this paradox could create diagnostic confusion and again emphasizes the potential errors that are created by reliance on resting measures and the clarity provided by exercise. Taken together, our results highlight the importance of exercise-based imaging approaches to unmask cardiac dysfunction in cancer survivors.
The relationship between exercise capacity and heart failure risk in cancer survivors is a matter of ongoing investigation. Pandey et al. [
37] reported that the greatest long-term risk of heart failure was observed in middle-aged adults with reduced exercise capacity and it is reasonable to speculate that those with markedly reduced exercise capacity as an adolescent would be at even greater risk. Peak VO
2 is determined by a combination of cardiac (central) and non-cardiac (peripheral) factors, and Houstis et al. [
38] have shown 97% of heart failure patients referred for exercise testing had significant limitation in both. Furthermore, it was estimated that complete reversal of cardiac impairment would only improve peak VO
2 by 7%, but complete improvement in peripheral oxygen extraction would improve peak VO
2 by 27% [
38]. This draws interesting parallels to the current study, where we observed survivors with reduced peak VO
2 had significant limitation in both cardiac function and peripheral oxygen extraction. Previous studies [
39,
40] have documented impairment in peripheral oxygen extraction in breast cancer patients receiving anthracycline- and/or taxane-based chemotherapy, however the existence of peripheral impairment in pediatric cancer survivors is a new and important finding. Given the majority of therapeutic strategies for heart failure prevention in cancer survivors are ‘cardiac focused’, these results highlight the need to investigate adjunctive therapies such as exercise training, that can address peripheral limitations [
40]. This also highlights the value of an integrative diagnostic measure such as peak VO
2, which is able to capture the central and peripheral defects that can contribute to exercise intolerance.
The primary limitation to this study is the modestly sized, heterogenous cohort. Whilst the modest cohort size increases the likelihood of a type I error, the alternative view that the differences noted in this study could represent a large effect size, should not be discounted. Indeed, the findings are not driven by outliers (Figs.
1 and
2), and the ability of our exercise measures to detect significant differences in cardiac function in such a small sample supports the higher sensitivity associated with exercise-based assessment of cardiac function. The small sample size also limits our ability to understand the relationships between host and treatment factors which are associated with reduced exercise capacity. Whilst participants had undergone varying degrees of cancer treatment, this represents the variety of real-world clinical contexts by which cancer survivors present with exertional intolerance. Additionally, the prognostic significance of the relationship between reduced peak VO
2 and cardiac reserve impairment in pediatric cancer survivors is unclear. Whilst we may speculate by drawing on parallels from other forms of heart failure, our findings require further validation to understand the prospective relationship between reduced peak VO
2 and clinical endpoints such as heart failure incidence and prognosis.
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