Review: Human Cardiac Tissue Models Accelerate Heart Attack Drug Development

Researchers from the University of Notre Dame have conducted a comprehensive review of the potential for human tissue models to improve treatment and diagnosis of heart attacks. They hope the work will illustrate recent advances in three-dimensional engineered infarction models and current regenerative therapeutic options, which can be used as a guide for developing new models and treatment strategies.

At 18 million deaths per year, heart attack is among the leading causes of mortality worldwide, and cases are expected to increase because of cardiovascular complications from COVID-19. Also called myocardial infarction, heart attacks occur when plaque in a major coronary artery slows down and blocks blood flow to the heart, depriving it of oxygen, killing cells, and leading to significant tissue damage. The result can be death or the build-up of scar tissue that makes future heart attacks more likely to result in death.

Although there has been some progress in heart attack treatment, translating pre-clinical findings to the clinic remains a major challenge. One reason for this is the lack of reliable and human representative healthy and fibrotic cardiac tissue models that can be used to understand the fundamentals of ischemic/reperfusion injury caused by heart attacks and to test new drugs and therapeutic strategies.

"Although animal models give an overall systemic view of how an organism would respond to a pathological condition, it is not the exact response that a human tissue would give," says Pinar Zorlutuna, Sheehan Family Collegiate Professor of Engineering at Notre Dame. "If you have a human model along with your animal model, chances are that you can catch discrepancies in between the two early on, before taking things to the clinical trial and failing there."

In vitro human models allow researchers to examine the impact of heart attacks and treatment of the fibrotic tissue outside the body. They use organoids, 3D organlike multicellular models derived from stem cells, to mimic natural development, structural organization, regeneration, and disease progression. Meanwhile, microfluidic devices control cell placement and fluid flow to act like the heart on a chip, while bioprinting allows cardiac tissue to be built up layer by layer.

Such models can accelerate preclinical research, getting therapeutics into more people in a faster, safer, and more efficient manner. But despite advances in tissue engineering, challenges remain to creating in vitro cardiac tissue models because the human heart is a very complex organ, says author Gozde Basara, a graduate student in Zorlutuna’s lab. "Larger constructs, engineered using mature cardiac cells and quick fabrication methods, would be the next step."

The article, published recently in Biophysics Reviews, discusses recent developments on pre-clinical infarct models, focusing mainly on the engineered three-dimensional cardiac ischemic/reperfusion injury and fibrosis models developed using different engineering methods such as organoids, microfluidic devices, and bioprinted constructs. The authors also present the benefits and limitations of emerging and promising regenerative therapy treatments for heart attacks. These include cell therapies, extracellular vesicles, and cardiac patches.

Zorlutuna and colleagues are currently using models to study and identify diagnostic markers for heart attacks. The strategy could be used to catch and prevent cardiovascular diseases in general