Microfluidics in heart-on-a-Chip platforms for cardiovascular drug discovery and cardiotoxicity assessment.

Cardiovascular disease remains the leading cause of death worldwide. However, the limited translational fidelity of traditional preclinical models continues to constrain the development of safer and more effective therapies. Animal studies and static two-dimensional cultures only partially reproduce human cardiac physiology, including mechanical loading, perfusion, multicellular interactions, and drug metabolism, which contribute to late-stage failure and unexpected cardiotoxicity. Accordingly, there is a growing need for human-relevant platforms that can more accurately model cardiac (patho)physiology, support drug discovery, and improve safety assessment. Microfluidic heart-on-a-chip (HoC) systems address this need by combining microfabrication, tissue engineering, and controlled fluid flow to generate miniaturized cardiac tissues with physiologically relevant biochemical, mechanical, and electrical cues. These platforms can provide real-time functional readouts, including contractility, electrophysiology, calcium handling, metabolic activity, and biomarker release, while also enabling the study of disease-relevant phenotypes such as ischemia-reperfusion injury, arrhythmias, fibrosis, and cardiomyopathy. In addition, HoC systems are increasingly being integrated with biosensors, automation, and multi-organ configurations to capture drug metabolism and inter-organ crosstalk, further improving their predictive value for efficacy and toxicity screening. In this review, we summarize the core design elements of microfluidic HoC platforms, highlight their applications in cardiovascular drug discovery and cardiotoxicity assessment, and discuss current challenges and future directions for the field.