Left Atrial Mechanics and Remodeling in Anthracycline-Treated Long-Term Survivors of Childhood Cancers

Professor Cheung, Yiu Fai   (Principal Investigator)

18

2015-04-01

80000

Left Atrial Mechanics and Remodeling in Anthracycline-Treated Long-Term Survivors of Childhood Cancers

anthracycline, atrial mechanics, childhood cancers

Cardiovascular Research

201409176033

Small Project Funding

2014

Completed

Survival from childhood cancer has increased significantly in recent decades. Long-term morbidities and mortality of survivors of childhood cancers remain nonetheless higher than the general population. Among the different causes, cardiovascular disease emerges as the most important one. Chronic cardiotoxicity of chemotherapeutic agents, in particular anthracyclines that has been widely used in treating paediatric solid tumours and haematological malignancies, is well documented. Regular cardiac assessment constitutes therefore an important part of long-term follow up for survivors of childhood cancers. Clinical protocols and previous research studies have focused, however, almost exclusively on assessment of ventricular systolic function. Nonetheless, reduced ejection fraction of the ventricle may be indicative of advanced rather than early cardiomyocyte damage. Several lines of evidence suggest potential involvement of the atrium in anthracycline cardiotoxicity. In an ovine model of anthracycline-induced cardiomyopathy, significant left atrial (LA) remodeling as characterized by atrial enlargement, dysfunction, and increased fibrosis has been reported. Anthracycline therapy has also been associated with development of atrial arrhythmias. In a group of middle-aged adults with previous anthracycline-based chemotherapy, increased ventricular myocardial extracellular volume, which reflects myocardial fibrosis, is found to be associated with greater LA volume and worse left ventricular (LV) diastolic function. In childhood cancer survivors, the reported ventricular diastolic dysfunction, albeit limited, may possibly also affect atrial mechanics. The clinical relevance of atrial dysfunction is increasingly recognized. Altered LA function has been found in patients with atrial fibrillation, LV dysfunction, and hypertension. Furthermore, LA enlargement has been shown to predict adverse cardiovascular outcomes in patients with congestive heart failure, stroke, transient ischaemic attack, and myocardial infarction. In the setting of LV dysfunction, atrial contribution becomes even more important. In patients with non-ischaemic dilated cardiomyopathy, there has been suggestion that contractile reserve impairment of the left atrium might precede that of the left ventricle. In patients with beta-thalassaemia major, atrial dysfunction has been shown to be more sensitive than depressed ventricular ejection fraction in identifying the burden of cardiac iron overload. In the setting of anthracycline cardiotoxicity, it is hence worthwhile exploring LA function as an early sensitive indicator of myocardial damage. Nonetheless, atrial function and its significance in long-term survivors of childhood cancer have hitherto not been examined. Optimal performance of the heart requires not only the ventricles but also the atria to fulfil their physiological roles. The atria transform continuous venous return into intermittent ventricular filling. They act as a reservoir during ventricular systole, function as a conduit during opening of the atrioventricular valve in early ventricular diastole, and perform as a pump during late ventricular diastole. The pump function of the atria depends in turn on electrical activation, electromechanical coupling, and synchronous contraction of the atrium. Additionally, a close relationship exists between morphology and function. Atrial fibrosis has been proposed to be involved in atrial remodeling. With accumulation of collagen as part of the reactive fibrosis or as a reparative process to replace degenerating myocardial tissue, deformation of the atrial wall might be affected. The magnitude and rate of atrial deformation may hence represent an early and noninvasive marker of the fibrosis remodeling. The absence of data on atrial function in anthracycline cardiotoxicity is related probably in part to the laborious methods required previously for assessment of atrial function. Recent advancements in non-invasive echocardiographic imaging technology have allowed convenient and comprehensive evaluation of functional and structural alteration of the atrium. The relatively angle independent speckle tracking echocardiography has been applied to the assessment of LA function. Determination of LA strain and strain rate, at different phases of the cardiac cycle provides a functional assessment of the reservoir, conduit, and pump function. Apart from functional assessment of atrial function, non-invasive modalities are available for assessment of LA fibrosis. Calibrated integrated back scatter (IBS) analysis is based on quantification of reflected ultrasound energy from the scattering elements of myocardial tissue to allow non-invasive tissue characterization. In patients with atrial fibrillation, calibrated IBS has been shown to correlate with the LA collagen content histologically, predict progression to persistent atrial fibrillation, and prognosticate the success of catheter ablation. Taken together, systematic evaluation of function and structural remodeling of the left atrium in long-term survivors of childhood cancers may offer new perspectives in the early detection of anthracycline cardiotoxicity. The primary objectives of the proposed study are (1) to test the hypothesis that anthracycline therapy for childhood cancers impairs left atrial mechanics and causes atrial remodeling, and (2) to determine potential interactions between left atrial and left ventricular mechanics in anthracycline-treated long-term survivors of childhood cancers. The key issues to be addressed in the proposed study in long-term survivors of childhood cancers include the followings: i. the effect of anthracycline therapy on left atrial reservoir, conduit, and pump function ii. the effect of anthracycline therapy on left atrial remodeling iii. potential interactions between left atrial and left ventricular mechanics