Vascular Assessment in Adult Survivors of Childhood Cancer: A St. Jude Lifetime Cohort Study Report

Abstract

Background: While end-organ toxicities following cancer therapy have been well described, long-term vascular health has received less attention.

Objectives: The purpose of this study was to evaluate vascular health in childhood cancer survivors (CCSs) utilizing established and novel biomarkers and measures of arterial function.

Methods: Serum biomarkers of inflammation (high-sensitivity C-reactive protein), hemostasis (fibrinogen, D-dimer, plasminogen activator inhibitor-1, tissue type plasminogen activator, von-Willebrand factor), and vasoregulation (surface and soluble vascular cell adhesion molecule-1 and P-selectin) were measured in this cross-sectional cohort study. Large and small arterial elasticity, pulse wave velocity, and augmentation index (AIx) were assessed. Differences between CCSs and sex- and age-matched controls were assessed in multivariable general linear regression models, adjusted for body mass index, race and ethnicity, smoking, and physical activity.

Results: Among 200 CCSs (median time from diagnosis 26.3 years [range: 11.2-47.9 years], current age 33.5 years [range: 19.3-61.6 years]) and 192 controls (33.3 years [range: 18.3-60.3 years]), plasminogen activator inhibitor-1 (1,804.7 pg/mL vs 1,577.9 pg/mL, P = 0.007) and endothelial surface expression of vascular cell adhesion molecule-1 (67.6% vs 43.5%; P < 0.001) and P-selectin (65.7% vs 45.9%; P < 0.001) were significantly elevated in CCSs compared to controls. Large artery elasticity (16.8 mL/mm Hg × 10 vs 18.1 mL/mm Hg × 10; P = 0.013) and small artery elasticity (7.1 mL/mm Hg × 100 vs 8.7 mL/mm Hg × 100; P < 0.001) were reduced, while pulse wave velocity (6.8 m/s vs 6.3 m/s; P < 0.001) and AIx (13.3% vs 8.1%; P < 0.001) were significantly elevated. AIx was higher among survivors exposed to chest radiation (15.4%) compared to those not exposed (11.2%).

Conclusions: CCSs have evidence of early vascular dysfunction, suggestive of premature atherogenesis.

Keywords: atherogenesis; childhood cancer survivors; endothelial dysfunction; vascular dysfunction.

Graphical abstract

Figure 1

Endothelial Cell Surface Expression of VCAM and P-Selectin in Childhood Cancer Survivors Compared to Controls Bar graphs show the mean endothelial cell surface expression of VCAM- and P-selectin in survivors (blue) compared to controls (yellow). Error bars represent 95% CIs and models are adjusted for body mass index, race, smoking status, and physical activity. VCAM = vascular cell adhesion molecule.

Figure 2

Augmentation Index in Childhood Cancer Survivors Treated With and Without Chest Radiation Box plots show the distribution of heart rate adjusted augmentation index in survivors treated with and without chest radiation. The median, IQR, and overall range are displayed and models are adjusted for age, body mass index, smoking status, low-density lipoprotein cholesterol, and anthracycline exposure.

Central Illustration

Atherogenesis in Cancer Survivors Compared to controls, survivors of childhood cancer demonstrate early signs of atherogenesis and arterial stiffness including increased PAI-1, increased surface expression of VCAM-1 and p-selectin, decreased arterial elasticity, and increased pulse wave velocity and augmentation index PAI = plasminogen activator inhibitor; other abbreviation as in Figure 1.