Phenotypic screening for new heart failure therapeutics: scalable animal modeling in zebrafish

Congestive heart failure (CHF) is a complex multi-organ syndrome representative of many chronic ‘diseases,’ and as such it has proven resistant to traditional cell-based drug discovery cannot readily be captured the relevant systemic biology. In vivo drug discovery screens offer unique opportunities to identify the initial dysfunction which ultimately drives heart failure (HF) and novel pathways modifying the cardiac response to injury. In this review, the author discusses phenotype-driven screens which allow rigorous and unbiased approaches to the biological systems which underpin HF (PubMed search terms on 07/11/2025-heart failure, cardiomyopathy, zebrafish, screen, drug). The rationale for specific models of HF and the relevance of the zebrafish in screens for suppressors of HF is discussed. Central principles are detailed for the successful design and execution of phenotypic screens for HF modifiers. A major focus is the development of scalable HF assays in the zebrafish. In vivo phenotypic screening in the zebrafish is a reproducible approach to the identification of potent suppressors of complex multisystem disorders including different forms of HF. Design features associated with success are the rigor and human fidelity of the initial mechanistic modeling and quantitative screen endpoints.