Novel echocardiographic interrogation of cardiovascular performance in long-term survivors of childhood cancers

Abstract

While incorporation of anthracyclines into chemotherapy protocols has significantly improved survival of paediatric cancer patients, their long-term cardiotoxic side effects are of concern. Deterioration of the commonly measured left ventricular (LV) ejection fraction (EF) at a resting state is nonetheless regarded as a late manifestation of cardiotoxicity. Important gaps, hence, exist with regard to cardiovascular monitoring in the long-term. While hitherto not been reported in survivors, advances in echocardiography including evaluation of myocardial stiffness using diastolic wall strain (DWS), myocardial strain imaging of LV, left atrial (LA), and right ventricular (RV), and exercise-stressed assessment of ventricular functional reserve and arterial function, may unveil early treatment-related alterations in cardiovascular function. The central hypothesis of this thesis is that novel echocardiographic modalities may help to unveil subclinical impairment of cardiovascular performance in long-term survivors of childhood cancers. Anthracycline-treated survivors of childhood malignancies aged 15 and above who had been off treatment for at least 5 years were recruited from Hong Kong. The demographic and echocardiographic findings were compared with those of healthy aged-matched control subjects. The findings of the five studies included in this thesis are described below. Survivors, despite having normal LV ejection fraction, had significantly lower LV DWS and greater LV calibrated integrated backscatter (cIB). Increased DWS was associated with greater LV cIB and impaired LV early diastolic deformation, while greater LV cIB was associated with impaired LV diastolic and torsional deformation. With regard to two-(2D) and three-(3D) myocardial strain imaging, LV mechanics were similar between female and male survivors, notwithstanding the worse LV myocardial deformation in survivors of both sex genders compared with sex-specific controls. Amongst all 2D and 3D strain parameters, 3D global longitudinal strain has the greatest area under the curve, implicating its sensitivity in the detection of subclinical cardiotoxicity in survivors. For LA mechanics, survivors had significantly lower peak negative LA strain and greater LA cIB than controls, coupled with lower LV shortening fraction, EF, mitral annular late diastolic velocity. Left atrial cIB further correlated positively with LV cIB. Exercise stress revealed blunting of the LV force-frequency relationship (FFR) and impairment of LV and RV systolic function reserve and LV diastolic functional reserve in survivors. Multivariate analysis revealed survivor status and baseline LV myocardial isovolumic acceleration as significant determinants of LV FFR. For arterial interrogation, arterial dysfunction including greater survivors had significantly greater carotid intima-media thickness and stiffness index, and higher central systolic blood pressure, and radial augmentation indices at rest and greater percentage increase in carotid stiffness at submaximal exercise than controls. Importantly, a steeper slope of increase in both carotid intima-media thickness and exercise-induced changes in carotid arterial stiffness with age in survivors implicate the possibility of accelerated vascular ageing among survivors. To conclude, these findings suggests increased LV myocardial stiffness, impaired LV, RV, and LA mechanics, impaired LV and RV functional reserves, and arterial dysfunction at rest and during exercise in anthracycline-treated survivors of childhood cancers. These impairments provide new perspectives on the current and future cardiovascular assessment in long-term paediatric cancer survivors.