They collapse without warning — on a track, on a field, mid-stride. Young athletes, often in peak condition, gone in an instant. For families, the shock is compounded by a cruel second discovery: the cause may be genetic, silently passed from one generation to the next.

“This disease was first discovered in Italy in a series of young people who had died suddenly while playing sport,” says Victoria Parikh, MD, a cardiologist at Stanford Department of Medicine. “You don’t see it coming. And then out of nowhere, a life is gone.”

She’s talking about arrhythmogenic cardiomyopathy, or ACM, a rare but devastating inherited heart disease. In its most common form, the heart’s muscle gradually breaks down and is replaced by fat and scar tissue. Caused by mutations in the PKP2 gene, the result is electrical chaos: dangerous arrhythmias that can send the heart racing at more than twice its normal rate, sometimes fatally.

For decades, treatment has meant managing risk rather than fixing the problem. Patients may receive implantable defibrillators, medications, or strict limits on physical activity. But nothing stops the disease itself. “Current management methods do not halt or reverse the progression,” says Parikh.

Now, Parikh and her colleagues are testing something more ambitious: a gene therapy designed to correct the underlying defect.

To accomplish this, researchers use a modified virus, stripped of its ability to replicate or cause disease. Instead, it acts as a delivery vehicle, carrying a small piece of DNA through the bloodstream and into the heart. Once inside a cell, the DNA travels to the nucleus, the cell’s command center, and begins producing the missing protein.

“The idea is that if you can deliver a new copy that’s functional,” Parikh explains, “you can potentially repair the heart, or, at the very least, prevent it from getting worse.”

That’s a bold claim about a disease where decline has long been considered inevitable.

A Small Trial, Cautious Optimism

So far, the study is small, consisting of about 10 participants across several U.S. centers, including Stanford. The patients are relatively young, many in their 20s and 30s, and already living with significant symptoms, including frequent arrhythmias.

Early results are encouraging.

On a molecular level, the therapy appears to be doing what it’s supposed to do. Researchers detected the delivered gene in heart tissue, along with increased production of the PKP2 protein. In theory, that should help restore the structural integrity of heart cells.

Clinically, the picture is more complex. Some patients showed reductions in dangerous heart rhythms; others did not. Measures of heart function remained largely stable, with modest improvements in some individuals.

But in a progressive disease, stability can be meaningful.

“What we’re super encouraged by,” Parikh says, “is that overall, they’ve done incredibly well. The safety of these therapies has been very reassuring.”

That may be the most important finding at this stage. Gene therapies carry risks, particularly immune reactions or unintended effects in other organs. In this trial, most side effects, such as temporary elevations in liver enzymes, were manageable with standard medications. 

From Diagnosis to Treatment

If the therapy ultimately proves effective, its implications could extend beyond currently enrolled patients.

Today, genetic testing for ACM is underused. One reason is pragmatic: confirming the diagnosis doesn’t necessarily change treatment. But that calculus shifts if a targeted therapy exists.

“Why make the genetic diagnosis,” Parikh asks, “if there’s nothing you can do with it?”

A successful gene therapy would change that. It would transform ACM from a condition managed reactively, after symptoms or cardiac events, into one treated proactively, guided by genetics.

In that sense, the trial is not just testing a drug. It’s testing a model of care: one where identifying a mutation leads directly to a therapy designed for it.

The Road Ahead

The HEROIC-PKP2 trial is still ongoing, with longer-term follow-up expected through 2027. Much remains uncertain. The study is small, not randomized, and designed primarily to assess safety. It will take larger trials (and time) to know whether the therapy can truly alter the course of disease.

Still, for patients and families who have lived under the shadow of sudden cardiac death, even cautious progress matters.

Because behind every data point is a story like the ones Parikh describes: a runner, a sibling, a child, someone who seemed perfectly healthy, until they weren’t. The hope now is that one day, those stories might become rarer. Not because the disease disappears entirely, but because it is finally understood, and, perhaps, treated at its source.