Promotion of Arterial Stiffness by Childhood Cancer and Its Characteristics in Adult Long-Term Survivors

Abstract

Background Vascular alterations induced by antineoplastic treatment might be considered as a possible underlying mechanism of increased cardiovascular sequelae in childhood cancer survivors (CCSs). We aimed to evaluate arterial stiffness among long-term CCSs and to compare the data against a population-based sample. Methods and Results Arterial stiffness was assessed by digital photoplethysmography (stiffness index; m/s) among 1002 participants of the CVSS (Cardiac and Vascular Late Sequelae in Long-Term Survivors of Childhood Cancer) study, diagnosed with neoplasia (1980-1990) before an age of 15 years. A population-based sample from the GHS (Gutenberg Health Study) (n=5252) was investigated for comparison. All subjects underwent a comprehensive, standardized clinical examination in the same study center. CCSs had higher stiffness index (β=0.66 m/s; 95% CI, 0.51-0.80 m/s) in multivariable linear regression analysis after adjustment for cardiovascular risk factors compared with the population sample of comparable age range. Stiffer vessels were found among CCSs also in absence of arterial hypertension (β=0.66; 95% CI, 0.50-0.81) or history of chemotherapy/radiotherapy (β=0.56; 95% CI, 0.16-0.96) in fully adjusted models. Moreover, stiffness index differed by tumor entity, with highest values in bone and renal tumors. Almost 5.2-fold higher prevalence of stiffness index values exceeding age-specific, population-based reference limits was observed among CCSs compared with GHS participants. Conclusions This is the first study demonstrating increased arterial stiffness among long-term CCSs. The data suggest that vascular compliance might differ in survivors of childhood cancer from the established development concept for arterial stiffness in the population; cancer growth and antineoplastic treatment might be relevant determinants of the pathobiological features. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT02181049.

Keywords: arterial stiffness; childhood cancer survivors; general population.

Figure 1. Age‐related increase of stiffness index in childhood cancer survivors and in the population.

Conditional density plots were generated and nonparametric bootstrap samples (n=1000) were run to estimate 95% CIs. Data were calculated on the basis of a CVSS (Cardiac and Vascular Late Sequelae in Long‐Term Survivors of Childhood Cancer) study sample, aged 30 to 45 years, and a GHS (Gutenberg Health Study) sample, aged 35 to 50 years.

Figure 2. Age‐ and sex‐adjusted arterial stiffness, according to tumor entity.

Data presented as age‐ and sex‐adjusted means for stiffness index, measured by digital photoplethysmography, with their 95% CIs. CNS indicates central nervous system.

Figure 3. Difference in stiffness index in childhood cancer survivors compared with a population sample, according to tumor entity.

Results from multivariable linear regression analysis with stiffness index as dependent variable and adjustment for age, sex, diabetes mellitus, arterial hypertension, smoking, obesity, dyslipidemia, and family history of myocardial infarction/stroke. Data presented as β estimates with their 95% CIs. CNS indicates central nervous system; ICCC3, International Classification of Childhood Cancer; and ref., reference.