Our current study demonstrated that asymptomatic PCS presented with significantly diminished exercise performance than controls despite normal global LV systolic function at rest and that the causes of their poor exercise performance are likely multifactorial. The simultaneous presentation of DHR/DWR and pOP indicated that PCS in general had higher dependency on HR increase than increase of OP at the peak exercise, suggesting primary limitation in stroke volume reserve. Peak RQ (= pVCO2/pVO2) was significantly higher in PCS than in controls, and a group of PCS with higher pRQ (≧1.3) revealed significantly lower pVO2* than PCS with lower pRQ (< 1.3), suggesting a limitation in aerobic capacity in some PCS. There were two small outlier groups of abnormal exercise performance in PCS with different underlying mechanisms. These findings represent the significant heterogeneity of abnormal cardiovascular presentation in PCS.
Decreased Exercise Performance in Asymptomatic PCS
Anthracycline-induced cardiotoxicity is a major cause of late cardiovascular complications in PCS that occur decades after the initial treatment . Late-onset cardiotoxicity is insidious and nonspecific yet progressive and irreversible . Thus, early recognition of cardiotoxicity is essential to protect patients from developing symptomatic cardiomyopathy or advanced heart failure. Reliability of echocardiogram in predicting late cardiovascular complications is limited as normal myocardial status in younger ages may not be completely free from late cardiotoxicity  . Indeed, treatment-mediated direct myocardial impairment may not be the only cause of long-term cardiovascular complications in PCS.
In this study, we demonstrated that peak exercise performance values including pVO2, pOP, and pWR were significantly lower in PCS than controls, in agreement with the previous published studies [6-9,15-18]. Two recent studies demonstrated no significant difference in parameters obtained by stress echocardiogram between PCS and age-matched controls at peak exercise [19,20], suggesting that markers of ventricular myocardial performance may not always be a sensitive marker of preclinical cardiovascular abnormality and that other peripheral factors, skeletal muscle alteration and/or vascular dysfunction, may also be contributing to a reduced exercise performance. Ness et al. studied 1041 adult survivors of childhood cancer and demonstrated high incidence of exercise intolerance (63.8%) due to a combination of cardiac, pulmonary, autonomic nervous system-mediated, and peripheral muscular impairment . A similar trend has been presented in adult breast cancer survivors with preserved LVEF, in which impaired peripheral vascular function and skeletal muscle dysfunction were attributed to decreased pVO2 in addition to impaired cardiac function . Worsening of exercise efficiency (high DVO2/DWR) may represent vascular dysfunction commonly seen in elderly people because of loss of vascular elasticity (vascular senescence) . Premature aging either by DNA damage or telomerase shortening in the cardiovascular system is suggested as a cause of increased incidence of cardiovascular events in PCS .
Possible Mechanisms of Preclinical Cardiotoxicity Characterized by CPET
From our current study, we propose certain underlying mechanisms responsible for the poor exercise performance in PCS. First, reduced pOP in PCS was noted in combination with preferential increase in HR in PCS (Figure 2). A limited stroke volume reserve with higher dependency on HR increase was previously reported in a small group of asymptomatic PCS . With an exercise MRI study, Foulkes et al. demonstrated that reduced peak exercise performance in PCS was associated with decreased stroke volume reserve and cardiac index . A combination of low pVO2 and high pRQ was noted to have significantly higher mortality in adult patients with chronic heart failure , suggesting that an impaired VO2 increase is a fundamental abnormality in PCS. In contrast, relatively lower pRQ was noted during an intense exercise in well trained athletes than that in sedentary controls . Collectively, a reduced peak oxygen delivery/consumption is a central pathophysiology in PCS regardless of identifiable global ventricular dysfunction, underscoring the critical importance of CPET in risk-stratifying asymptomatic PCS.
Second, there may be a difference in the composition of metabolically active skeletal muscle mass between PCS and controls, as shown in Figure 1, although we were not able to demonstrate statistical significance. Sarcopenia and skeletal muscle dysfunction are known complications after cancer treatment [29,30]. A difference in capillary density and mitochondria concentration within the myocytes can also affect oxygen utilization at a tissue level . Repetitive skeletal muscle contraction is also known to augment venous return and thus cardiac output (muscle pump). It is plausible that PCS are more prone to inactive lifestyle responsible for physical deconditioning . Altered peripheral oxygen utilization may contribute to poor exercise performance despite normal ventricular systolic function in some PCS.
Lastly, there were small subgroups of outliers of high DVO2/DWR and low DVO2/DWR (group a and b in Figure 6B, respectively). High DVO2/DWR implies a high oxygen cost to perform external work, commonly seen in obesity, use of additional muscles, or recruitment of less efficient muscle fibers . These people showed comparable exercise performance with the rest but had decreased peak WR and significantly increased HR dependency similar to group b. A combination of low DVO2/DWR and low pVO2 indicates decreased cardiac output frequently seen in patients with chronic heart failure  and should be regarded as a high-risk group. Although obese subjects were not included in this study, it is plausible that some PCS with decreased skeletal muscle mass and presumably increased body fat present with elevated DVO2/DWR.
Application of Simultaneous Assessment by Two CPET Parameters
We have characterized a new method of assessing CPET data by combining peak and submaximal parameters (including weight) simultaneously to compare the trends of two groups (“Two-dimensional CPET Analysis”). These submaximal parameters are useful and informative but have been underutilized in conventional pediatric CPET analysis.
A simultaneous assessment of DHR/DWR and pOP (= a surrogate of stroke volume at peak exercise) or pVO2 showed not only a good inverse relationship between the two parameters but also demonstrated a clear difference between PCS and controls (Figure 2). Submaximal parameters, VAT, OUES, and DVO2/DHR, were plotted with pVO2 in both groups, which showed an excellent positive correlation with almost identical correlation lines, suggesting that these submaximal parameters are reliable markers to predict peak exercise performance in both groups (Figure 3). Two-dimensional analyses by DVO2/DWR and pVO2* further identified two distinctive outliers in PCS: one with probably inefficient peripheral energy production (group a) and the other with limited ventricular myocardial reserve with lower aerobic capacity (group b) (Figure 6). The two-dimensional CPET correlation analysis is easy to perform even retrospectively from any existing standard exercise worksheet and provides substantial additional information to interpret baseline exercise physiology without extra investment .
There are several limitations in our study that need to be addressed. This is a retrospective study with a relatively small sample size in a single center. The PCS group represents a heterogeneous population regarding primary diagnosis, cumulated dosage of anthracycline, years at diagnosis, years after remission, body habitus, and the level of baseline physical activities. Notably, physical conditioning was not specifically addressed in either group. Skeletal muscle mass was not directly measured, which could affect the interpretation of CPET results. There may be a selection bias as PCS included in this study were those who were willing undergo CPET for functional assessment of their exercise performance. We also excluded the obese PCS from the study primarily to optimize the CPET interpretation as obesity may be an important pathological feature in PCS. Despite these limitations, our current study clearly underscores the primary involvement of the reduced stroke volume with heterogenous abnormalities other than direct myocardial impairment in otherwise asymptomatic PCS.