Risk factors for future cardiac diseases in childhood cancer survivors

Background. With 12,000 children diagnosed with cancer annually in the United States and survival rates approaching 80%, the long-term health of childhood cancer survivors is an increasingly important concern. This is especially true given that over 70% of survivors develop a chronic health condition by 30 years after their original diagnosis. Cardiovascular diseases (CVD) are the most common non-cancer related complications. Although some risk factors for therapy-induced cardiovascular damage have been identified, their influence on longitudinal CVD risk is not well described, and therefore, their clinical utility is limited. While guidelines exist for protecting the long-term cardiovascular health of survivors, they are generalized from general population recommendations, placing a strong reliance on healthy lifestyle habits such as diet. By failing to consider the clinical heterogeneity of survivors, these recommendations may miss those survivors with the greatest need for risk management and ignore the possibility that survivors require unique strategies for effective CVD prevention. It is also unclear how a history of childhood cancer affects diet, how diet in-turn affects the development of traditional CVD risk factors among survivors, and what the combined effects of these traditional CVD risk factors imply for the long-term health of survivors.;Methods. This dissertation presents results from 3 investigations related to the long-term cardiovascular health of survivors using data from the Cardiac Risk Factors in Pediatric Cancer Survivors Study. This study included 201 survivors, a median of 11 years from cancer diagnosis, and 76 of their siblings who were assessed during day-long study visits including echocardiography, patient histories, and laboratory tests conducted from 1999 to 2003. Cancer treatment records were reviewed and 3-day food records collected. First, the associations between cranial irradiation and cardiac abnormalities associated with anthracycline chemotherapy were examined. Associations with insulin-like growth factor 1 (IGF-1), a marker of growth hormone, were also examined. Second, diet records were used to estimate daily caloric intake relative to recommended levels and dietary quality using the Healthy Eating Index-2005 (HEI). The diets of survivors and siblings were compared and associations with cancer types and treatments investigated. The association between dietary quality and adiposity among survivors was also examined. Third, future CVD risk due to traditional CVD risk factors was examined using Pathobiological Determinants of Atherosclerosis in Youth (PDAY) scores and the Framingham Risk Calculator (FRC), both expressed as ratios relative to an individual of similar age and sex without modifiable risk factors. The PDAY odds ratio represents the increased odds of currently having an advanced coronary artery lesion. The FRC risk ratio represents the increased risk of a myocardial infarction, stroke, or coronary death in the next 30 years. Survivor and sibling risk estimates were compared and associations with cancer diagnoses and treatments as well as physical inactivity examined.;Results. Survivors exposed to cranial radiation had an additional 12% decrease in LV mass compared to unexposed survivors (P<.01), and an additional 3.6% decrease in LV dimension (P=.03). Survivors exposed to cranial radiation also had a greater decrease in IGF-1 relative to normal levels than unexposed survivors (30.8% vs. 10.5% decrease, P<.01). There were no differences between survivors and siblings in daily caloric intake (97 vs. 105% of recommended caloric intake) or the HEI total score (55.5 vs. 53.3), respectively. Survivors exposed to cranial radiation had lower total HEI scores (-6.4, P=.01). Among survivors, increasing dietary quality was associated with decreasing percent body fat (beta=-.19, P=.04). The median PDAY odds ratio for survivors was 2.2 (interquartile range, 1.3--3.3). The median FRC risk ratio was 1.7 (interquartile range, 1.0--2.0). Survivors and siblings had similar mean PDAY odds ratios (2.33 vs. 2.29, P=.86) and FRC risk ratios (1.72 vs. 1.53, P=.24). Cancer type and treatments were not associated with the CVD risk estimated from traditional metabolic CVD risk factors, cardiometabolic health. There was a suggested association of physical inactivity with PDAY odds ratios (r=0.17, P=.10) and FRC risk ratios (r = 0.19, P=.12).;Discussion. Among anthracycline-treated survivors, those with cranial radiation exposure had significantly greater decreases in LV mass and dimension. Because cranial irradiation was also associated with decreased IGF-1, it is possible that GH deficiencies mediated this effect suggesting that GH replacement therapy may help prevent the development of cardiotoxicity. Survivors consumed diets similar in quality to their siblings though both groups were only moderately adherent to guidelines. Dietary quality was associated with increased body fat in survivors suggesting interventions focused on diet quality may help reduce their adiposity. Cardiometabolic health was poor in survivors but not different than that of their siblings, highlighting the importance of managing traditional CVD risk factors and considering novel exposures in survivors.