Modified human heart tissue shows researchers mechanisms of tachycardia

Heart rate is easier to monitor today than ever. With smartwatches capable of pulse detection, it only takes a flick of the wrist to check your heart. But monitoring the cells responsible for heart rate is much more difficult, and that encourages researchers to invent new ways to analyze them.

Joseph Wu, MD, Ph.D., director of the Stanford Cardiovascular Institute and professor of medicine and radiology, designed a new stem cell-derived model of heart tissue that provides insight into the conditions that occur when heart cells die . control. In particular, Wu is studying a disorder called tachycardia, which increases heart rate and can lead to cardiomyopathy, in which the heart loses its ability to sufficiently pump blood in people with otherwise healthy heart structures.

“Tachycardia is probably more common than we think,” said postdoctoral researcher Chengyi Tu, Ph.D., who helped lead the work. “It is thought to be underdiagnosed because an increase in heart rate is quite common in different types of heart disease and it is masked.”

To study tachycardia-induced cardiomyopathy, researchers engineered heart cells from human stem cells to discover how our body’s engine works when it’s in overdrive.

“Modeling tachycardia-induced cardiomyopathy with heart tissue derived from human stem cells allows us to better understand the impact of fast heart rates on our bodies,” said Wu, Simon H. Stertzer, MD, professor and author. principal of the study. . It was published on November 27 in Natural biomedical engineering. You are the main author.

Cardiac cell engineering

Unlike most types of body tissue, heart cells are extremely difficult to grow in the laboratory. Patient heart cells grown in a dish tend to dedifferentiate – or lose their main function and no longer beat.

“Ideally, you want to take samples from a patient’s heart right after the disease is diagnosed, during the disease and after treatment,” Tu said. “To validate your finding, you need a lot of replicates to give you statistical power, but clinically it’s impossible to sample that frequently.”

Given the shortage of tissue, Wu and his colleagues cultured more than 400 heart tissue samples from stem cells to study how heart cells function, a process that took more than four years.

“Creating engineered heart tissue is very different from growing cells in a dish. The lead time is very long,” Tu said. Generating heart cells from stem cells takes about two weeks; assembling them into a 3D fabric and maturing them takes almost two months.

Restore chemical balance

Using a wire chamber, the researchers electrically stimulated the cells, inducing tachycardia. They tested whether the cells could recover from tachycardia within 10 days. Over the first five days, the cells’ ability to contract continually declined to about 50% of their normal function. But once the researchers stopped the electrical stimulation, the cells fully recovered within five days.

This fits with what doctors already know about tachycardia-induced cardiomyopathy: it is largely reversible. When a person’s heart rate slows, the function of their heart tissue returns to normal.

In another experiment, the researchers induced tachycardia in a different group of engineered heart tissue. Then, after stopping stimulation, the team supplemented the tissues with NAD – a molecule that supports energy reactions – and saw heart cell function recover more quickly. The supplemented tissues had recovered 83% of their original function by the first day, while the untreated group showed little improvement.

To validate their results, the team compared the engineered heart tissues with human clinical data and data from canine models. “I was surprised to see how well the artificial heart tissues mimic real human hearts,” Tu said.

Discover the molecular switch

During tachycardia, the heart may have trouble pumping blood to the rest of the body because the fast heart rate prevents the heart chambers from fully filling and contracting. If this persists for several days or weeks, which can happen in severe cases, the blood vessels stop supplying enough oxygen to the heart tissue and the rest of the body.

When beating normally, the heart uses fat as a source of energy, but breaking it down requires a lot of oxygen. Without oxygen, the heart’s fuel source changes to sugar in a process called metabolic rewiring. Fuel switching and hypoxia, or lack of oxygen, contribute to a decrease in the NAD/NADH ratio, a vital chemical duo that helps maintain the function of a heart tissue protein known as SERCA.

“Different levels of SERCA protein act like an accelerator and brake pedal for a car,” Tu said. When researchers increase the amount of NAD, the heart’s gas pedal is pushed and the protein SERCA strengthens the heartbeat of the modified cells. When they decrease, the artificial heart tissues slow down, making them beat more weakly.

By administering NAD to patients through a commercially available supplement or by IV injection, clinicians believe they can restore chemical balance and speed the patient’s recovery.

Along with a possible new supplement to help patients recover from tachycardia, the research demonstrates the importance of new methods for modeling the disease. Last year, President Joe Biden signed into law the FDA Modernization Act 2.0, which removed the requirement for animal testing before human drug trials.

“Now there is more need for non-animal models to complement animal models,” Tu said. “This work proves that it is possible to model complex heart conditions using a universal non-animal model to study this disease and test possible therapies.”