Functional and transcriptomic analysis of a zebrafish model of heart failure induced by isoproterenol

Heart failure is a complex cardiac disorder characterized by ventricular dilation and disruption of the cardiac performance. After a cardiac injury, such as a myocardial infarction, the activation of sympathetic and adrenergic systems attempts to maintain cardiac output. However, sustained elevation of circulating catecholamines triggers maladaptive changes in the heart that eventually lead to heart failure. Chronic isoproterenol treatment is a well-established approach to mimic the development of heart failure in animal models to study pathophysiological mechanisms. Here, we induced heart failure in zebrafish by exposing larvae from 3 to 14 days post-fertilization (dpf) to isoproterenol and then monitored cardiac function, Ca2+ homeostasis and mitochondrial ATP levels. We found that larvae at 7 and 14 dpf developed heart failure with significant bradycardia, reduced Ca2+ level and contractility. Interestingly, the cardiac dilation observed in 7 dpf larvae compensated stroke volume and maintained a cardiac output like controls, whereas the cardiac output dropped in 14 dpf larvae with heart failure . Thus, two clinical stages were identified in the zebrafish larvae, compensated, and decompensated heart failure at 7 and 14 dpf, respectively. Transcriptomic analysis by RNA sequencing of the 14 dpf failing hearts revealed the onset of cardiac remodeling involving epigenetic changes, a proinflammatory response, alteration in sarcomere proteins and metabolism. Mitochondrial structure and functions were affected in the failing hearts, suggesting a key role in the development of decompensated heart failure.