Restoration of cardiac function after anaemia-induced heart failure in zebrafish

Aims: New therapeutic approaches are needed to fight against the growing epidemic of heart failure. Unlike mammals, zebrafish possess the incredible ability to regenerate cardiac tissue after acute trauma such as apical resection. Yet, the ability of zebrafish to recover after a chronic stress leading to heart failure has not been reported. The aim of this study was to test whether zebrafish can recover a normal cardiac function after anaemia-induced heart failure. Methods and results: Eight- to ten-month-old zebrafish were treated with phenylhydrazine hydrochloride, an anaemia inducer, to generate heart failure. Treatment was stopped after 5 weeks and fish were followed-up for 3 weeks. Assessment of ventricular function by ultrasound at the end of the treatment revealed an increase in ventricle diameter (+47%) and a decrease in heart rate (−36%) and fractional shortening (−30%). A decrease in swim capacity was also observed (−31%). Tissue staining showed a thickening of the ventricular wall (5-fold), cell apoptosis and proliferation but no fibrosis. Expression of foetal genes, angiogenic factor and inflammation markers was increased, and β-adrenergic receptor-1 was decreased. Three weeks after phenylhydrazine hydrochloride withdrawal, all parameters returned to baseline and the fish recovered a normal cardiac function, tissue morphology and gene expression. Conclusions: Zebrafish are able to completely recover from anaemia-induced heart failure. This model represents a unique opportunity to investigate the mechanisms of cardiac repair and may lead to the discovery of novel therapeutic targets of heart failure.