Scientists are now able to create cardiac heart muscle cells from patients with heart disease. But cells alone aren’t enough to fully study cardiac disorders — especially rhythm disorders that require the activity of multiple cells assembled into tissues.
William Pu, MD, of Boston Children’s Hospital’s Heart Center and his team are honing the art of modeling heart disease in a dish. With an accurate lab model, they hope to test drug therapies without posing a risk to living patients (or even live animals).
Together with researchers at Harvard’s Wyss Institute, Pu’s lab recently modeled a rare rhythm disorder called catecholaminergic polymorphic ventricular tachycardia (CPVT). CPVT is a dangerous disease in which the heart’s rhythm can suddenly jolt abnormally without warning. Undetectable on a resting electrocardiogram (EKG), CPVT does not affect patients at rest. However, exercise or emotional upset trigger high levels of adrenaline, which can lead to life-threatening arrhythmia, cardiac arrest and possibly sudden death.
Building the tissue model
Isolated CPVT heart muscle cells don’t capture many of the features observed in the actual disorder, so Pu and colleagues created a living tissue model. They first took skin cells from patients with CPVT and transformed them into pluripotent stem cells. Next, they turned the stem cells into heart muscle cells. Finally, they teamed up with bioengineers from the lab of Kit Parker, PhD at the Wyss Institute to build the heart tissue.
The team induced the heart muscle cells to line up like tiny rectangles in parallel lines. The engineered heart tissues conducted electricity straight along those lines, recreating what happens in native heart tissue.
But to simulate the effect of exercise, the team needed a way to pace the heart rhythm. Pu, Parker and colleagues achieved this by using a protein that causes the heart muscle cells to beat in response to light, a technique known as optogenetics. “We can control the tissue with light,” explains Pu.
Arrhythmia in a dish
The team next combined rapid flashes of light and an adrenaline-like chemical to simulate exercise. “It’s like an exercise test in a dish,” Pu says.
The model has allowed Pu’s team to observe what happens at a tissue level when a CPTV patient exercises. They replicated the abnormal circular rhythms in CPVT heart muscle tissue, creating a tissue level equivalent of cardiac arrest.
Using this model, the team is looking to identify ways to prevent the rhythm disturbance triggered by adrenaline. “We want to figure out which proteins controlled by the adrenaline receptor are most important,” says Pu. “Is there some subset that interacts with the CPVT mutation to cause the arrhythmia? We’re hopeful this model will offer insight into new treatments.”
Precision prescribing for heart disease?
In addition to finding new treatments, another important application could be testing a patient’s response to medication before it’s prescribed, says Pu.
For example, some CPVT patients have seen positive improvements with a medication called flecainide, “but we can’t predict which patients will respond well to it,” says Pu. “If we could take a sample of someone’s skin cells, create a personalized model of that person’s CPVT mutation and test the effect of flecainide, we could avoid the risk of side effects in patients who would not respond.”
If these cell/ tissue models can reliably predict a patient’s response to different therapies, they could revolutionize pediatric cardiology. Each individual’s treatment could be determined by his or her unique biology.
Pu’s group is also eager to test the modeling process with other types of heart rhythm disorders. Next up: Long QT syndrome and arrythmogenic cardiomyopathy, which are both slightly more common than CPVT.
Pu is enthusiastic about how new techniques in basic research are integrating his lab’s work more closely with clinical treatments. “As technology evolves,” he says, “there’s more opportunity to collaborate with clinicians to advance patient care.”