Childhood cancer and future cardiometabolic health

Figures

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  Fig. 1. Mechanisms and long-term cardiometabolic sequelae of cancer therapies in childhood and adolescence. Cancer therapies commonly used during childhood and adolescence can cause long-term cardiovascular and metabolic complications through distinct but overlapping mechanisms. Anthracyclines induce oxidative stress, topoisomerase IIβ inhibition, and cardiomyocyte apoptosis and senescence, leading to structural and functional cardiac abnormalities and an increased risk of cardiomyopathy and heart failure. Radiotherapy can damage the heart and vasculature, disrupt hypothalamic–pituitary function, and alter whole-body metabolism, increasing the risk of atherosclerosis, coronary artery disease, valvular disease, arrhythmias, and heart failure. Haematopoietic stem cell transplantation (HSCT), particularly when combined with prior chemotherapy or total body irradiation, contributes to chronic inflammation, immune dysregulation, endocrine dysfunction, and adverse metabolic profiles, resulting in elevated risks of early-onset cardiovascular disease and metabolic disorders. This figure was created with BioRender. ROS reactive oxygen species, HSCT haematopoietic stem cell transplantation.

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  Fig. 2. Late mortality and integrated cardiometabolic profile in survivors of childhood cancer. A Causes of late mortality at 40 years after childhood cancer diagnosis in survivors from North America compared with the general population. B Integrated cardiometabolic profile of childhood cancer survivors, spanning cardiac dysfunction (reduced left‑ventricular ejection fraction, together with raised NT‑proBNP, a marker of myocardial wall stress, and reduced GLS, an early indicator of impaired systolic deformation), cardiometabolic risk factors (increased body weight and fat mass and metabolic syndrome components), reduced cardiorespiratory fitness with exercise intolerance, and gut dysbiosis with lower alpha‑diversity and depletion of anti‑inflammatory, butyrate‑producing taxa such as Faecalibacterium. This figure was created with BioRender. GLS global longitudinal strain, MetS metabolic syndrome, NT-proBNP N-terminal pro-B-type natriuretic peptide, SMR standardised mortality ratio, VO2peak peak oxygen uptake (typically assessed during cardiopulmonary exercise testing until volitional exhaustion).

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  Fig. 3. Key determinants of cardiometabolic health, beyond cancer treatment-related exposures, in survivors of cancer diagnosed during childhood or adolescence. These determinants include genetic, epigenetic, biological, social, and lifestyle-related factors that jointly shape long-term cardiometabolic risk. Genetic and epigenetic susceptibility includes risk variants (e.g., rs6689879 at 1p13.2 and rs2229774 in RARG) and epigenetic age acceleration, which may modulate susceptibility to treatment‑related cardiometabolic injury. The left-hand panel shows the domains that shape cardiometabolic health; the right-hand panel lists the specific factors within these domains that have been associated with higher cardiometabolic risk in this population. This figure was created with BioRender. RARG retinoic acid receptor gamma.

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  Fig. 4. Lifestyle habits (physical activity and nutrition) in patients with (or survivors of) childhood/adolescent cancer, contrasting healthy and unhealthy patterns and their associated outcomes. A healthy lifestyle and balanced energy state are associated with fewer cardiovascular events and lower all‑cause mortality, whereas physical inactivity and energy imbalance promote adiposity (or, in some patients, undernutrition) and associated cardiometabolic risk factors. This figure was created with BioRender.