Cardiovascular status of childhood cancer survivors exposed and unexposed to cardiotoxic therapy

Abstract

Purpose: To determine whether cardiovascular abnormalities in childhood cancer survivors are restricted to patients exposed to cardiotoxic anthracyclines and cardiac irradiation and how risk factors for atherosclerotic disease and systemic inflammation contribute to global cardiovascular status.

Methods: We assessed echocardiographic characteristics and atherosclerotic disease risk in 201 survivors of childhood cancer with and without exposure to cardiotoxic treatments at a median of 11 years after diagnosis (range, 3 to 32 years) and in 76 sibling controls.

Results: The 156 exposed survivors had below normal left ventricular (LV) mass, wall thickness, contractility, and fractional shortening and above normal LV afterload. The 45 unexposed survivors also had below normal LV mass overall, and females had below normal LV wall thickness. Exposed and unexposed survivors, compared with siblings, had higher levels of N-terminal pro-brain natriuretic peptide (81.7 and 69.0 pg/mL, respectively, v 39.4 pg/mL), higher mean fasting serum levels of non-high-density lipoprotein cholesterol (126.5 and 121.1 mg/dL, respectively, v 109.8 mg/dL), higher insulin levels (10.4 and 10.5 μU/mL, respectively, v 8.2 μU/mL), and higher levels of high-sensitivity C-reactive protein (2.7 and 3.1 mg/L, respectively, v 0.9 mg/L; P < .001 for all comparisons). Age-adjusted, predicted-to-ideal 30-year risk of myocardial infarction, stroke, or coronary death was also higher for exposed and unexposed survivors compared with siblings (2.16 and 2.12, respectively, v 1.70; P < .01 for both comparisons).

Conclusion: Childhood cancer survivors not receiving cardiotoxic treatments nevertheless have cardiovascular abnormalities, systemic inflammation, and an increased risk of atherosclerotic disease. Survivorship guidelines should address cardiovascular concerns, including the risk of atherosclerotic disease and systemic inflammation, in exposed and unexposed survivors.

Fig 1.

(A-C) Serum levels of cardiac biomarkers by cancer treatment history and sex. Box plots show the minimum, maximum, interquartile range (box), and median values for survivors of childhood cancer exposed or unexposed to known cardiotoxic treatments and for sibling controls, by sex. HDL, high-density lipoprotein; hs-CRP, high-sensitivity C-reactive protein; NT-proBNP, N-terminal pro-brain natriuretic peptide.

Fig 2.

(A-C) Correlations between serum levels of cardiac biomarkers in survivors of childhood cancer. Bivariate histograms show the number of survivors of childhood cancer on the vertical axes in each quartile-quartile bin for the biomarker quartiles listed on the diagonal axes. Each bar represents the number of survivors who were in a specific quartile-quartile pair for each of the biomarkers listed on the two diagonal axes. The bars in any one row should add to the total in that quartile for the biomarker listed on the referent axis. Spearman's rank correlation coefficient and associated P value are also reported for the association between these biomarkers. HDL, high-density lipoprotein; hs-CRP, high-sensitivity C-reactive protein; NT-proBNP, N-terminal pro-brain natriuretic peptide.

Fig A1.

Scatter plots of left ventricular (LV) structure and function by N-terminal pro-brain natriuretic peptide (NT-proBNP) and high-sensitivity C-reactive protein (hs-CRP) in survivors of childhood cancer by exposure to known cardiotoxic treatments. Scatter plots show the paired values for specific echocardiographic characteristics and serum biomarkers with a linear regression line overlaid. Partial Spearman's rank correlation coefficients (ρ), with the effect of the other biomarker removed, and associated P values are also reported for the associations between these biomarkers and echocardiographic characteristics. Ln, natural logarithm.