Toward Functional Screening of Cardioactive and Cardiotoxic Drugs with Zebrafish in Vivo Using Pseudodynamic Three-Dimensional Imaging

Abstract

Given the high mortality in patients with cardiovascular diseases and the life-threatening consequences of drugs with unforeseen adverse effects on hearts, a critical evaluation of the pharmacological response of cardiovascular function on model animals is important especially in the early stages of drug development. We report a proof-of-principle study to demonstrate the utility of zebrafish as an analytical platform to predict the cardiac response of new drugs or chemicals on human beings. With pseudodynamic 3D imaging, we derive individual parameters that are central to the cardiac function of zebrafish, including the ventricular stroke volume, ejection fraction, cardiac output, heart rate, diastolic filling function, and ventricular mass. We evaluate both inotropic and chronotropic responses of the heart of zebrafish treated with drugs that are commonly prescribed and possess varied known cardiac activities. We reveal deranged cardiac function of a zebrafish model of cardiomyopathy induced with a cardiotoxic drug. The cardiac function of zebrafish exhibits a pharmacological response similar to that of human beings. We compare also cardiac parameters obtained in this work with those derived with conventional 2D approximation and show that the latter tends to overestimate the cardiac parameters and produces results of greater variation. In view of the growing interest of using zebrafish in both fundamental and translational biomedical research, we envisage that our approach should benefit not only contemporary pharmaceutical development but also exploratory research such as gene, stem cell, or regenerative therapies targeting congenital or acquired heart diseases.