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Cardiopulmonary Exercise Testing Characterizes Silent Cardiovascular Abnormalities in Asymptomatic Pediatric Cancer Survivors

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Abstract

Late-onset cardiovascular complications are serious concerns for pediatric cancer survivors (PCS) including those who are asymptomatic. We investigated whether cardiopulmonary exercise testing (CPET) can delineate the underlying pathophysiology of preclinical cardiovascular abnormalities in PCS. We examined CPET data via cycle ergometer in asymptomatic PCS with normal echocardiogram and age-matched controls. Peak and submaximal parameters were analyzed. Fifty-three PCS and 60 controls were studied. Peak oxygen consumption (VO2), peak work rate (WR), and ventilatory anaerobic threshold (VAT) were significantly lower in PCS than controls (1.86 ± 0.53 vs. 2.23 ± 0.61 L/min, 125 ± 45 vs. 154 ± 46 W, and 1.20 ± 0.35 vs. 1.42 ± 0.43 L/min, respectively; all p < 0.01), whereas peak heart rate (HR) and ventilatory efficiency (a slope of minute ventilation over CO2 production or ∆VE/∆VCO2) were comparable. Peak respiratory exchange ratio (RER) was significantly higher in PCS (p = 0.0006). Stroke volume (SV) reserve was decreased in PCS, indicated by simultaneous higher dependency on HR (higher ∆HR/∆WR) and lower peak oxygen pulse (OP). Twelve PCS with high peak RER (≥ 1.3) revealed lower pVO2 and VAT than the rest of PCS despite higher ventilatory efficiency (lower ∆VE/∆VCO2), suggesting fundamental deficiency in oxygen utilization in some PCS. Poor exercise performance in PCS may be mainly attributed to limited stroke volume reserve, but the underlying pathophysiology is multifactorial. Combined assessment of peak and submaximal CPET parameters provided critical information in delineating underlying exercise physiology of PCS.

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Acknowledgements

We thank the Nemours Summer Student Research Program offered by Nemours Children’s Health, Wilmington, DE (for A. G.). We also acknowledge DE-CTR ACCEL program for biostatistics support. The authors thank Ms. Theresa Michel for editing the manuscript text.

Funding

Authors received no external funding for this study.

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Authors and Affiliations

  1. Nemours Cardiac Center, Nemours Children’s Health, 1600 Rockland Rd, Wilmington, DE, 19803, USA

    Takeshi Tsuda, Daphney Kernizan, Austin Glass & Gina D’Aloisio

  2. Division of Biostatistics, Nemours Children’s Health, Wilmington, DE, 19803, USA

    Jobayer Hossain

  3. Division of Hematology & Oncology, Nemours Children’s Health, Wilmington, DE, 19803, USA

    Joanne Quillen

  4. Department of Pediatrics, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, PA, 19107, USA

    Takeshi Tsuda

  5. Department of Engineering, Saint Louis University, Saint Louis, MO, 63103, USA

    Austin Glass

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Contributions

TT primarily conceptualized and designed the study and organized the research team. Material preparation, data collection, and analysis of cardiopulmonary exercise testing (CPET) were performed by TT, DK, AG, and GD’A. JH is a biostatistician who carefully analyzed the entire data and provided critical suggestions regarding statistics. JQ oversees the Oncology Survivorship Program, which provided the patients’ medical information regarding diagnosis and treatment of primary disease and their current clinical status. The first draft of the manuscript was written by TT, and all authors commented on the manuscript. All authors read and approved the final manuscript.

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Correspondence to Takeshi Tsuda.

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246_2022_2995_MOESM1_ESM.pptx

Supplementary file1 (PPTX 72 KB)—Supplemental Figure 1. Submaximal slope parameters. A A cardiopulmonary exercise test (CPET) worksheet of a 17-year-old male with acute lymphoblastic leukemia (ALL) who is now off-treatment. B A slope of work rate (WR) and oxygen consumption (VO2) (∆VO2/∆WR). C A slope of WR and heart rate (HR) (∆HR/∆WR). D A slope of HR and VO2* (∆VO2*/∆HR). E Oxygen uptake efficiency slope (OUES), where x-axis is log10[minute ventilation (VE)] and y-axis is VO2, and F A slope of minute ventilation (VE) and VCO2. There is an excellent correlation among these parameters during submaximal exercise phase.

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Tsuda, T., Kernizan, D., Glass, A. et al. Cardiopulmonary Exercise Testing Characterizes Silent Cardiovascular Abnormalities in Asymptomatic Pediatric Cancer Survivors. Pediatr Cardiol 44, 344–353 (2023). https://doi.org/10.1007/s00246-022-02995-w

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