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More people are dying of a ‘stiff’ heart, and no drugs can fix it. This Penn team has a new approach

Heart failure plays a role in 1 out of 8 deaths in the United States. Researchers have new ideas to reduce the burden on the body's pump.

Ben Prosser and colleagues at Penn showed they can boost the contracting ability of a diseased heart cell. The key is a scaffold-like network of filaments called microtubules, shown in blue.
Ben Prosser and colleagues at Penn showed they can boost the contracting ability of a diseased heart cell. The key is a scaffold-like network of filaments called microtubules, shown in blue.Read moreTIM TAI / STAFF PHOTOGRAPHER

A few dozen times a year at the Hospital of the University of Pennsylvania, a medical team is mobilized to take charge of a precious gift: a donated human heart that will be transplanted into the body of a gravely ill patient.

Behind the scenes, a second team often goes to work on another valuable resource: the damaged heart that has been removed.

The injury may have resulted from a heart attack. Or, something went haywire with the electrical and chemical signals that drive the organ to pump more than two billion times in a typical lifetime. High blood pressure, diabetes, or genetic abnormalities might have played a role.

Studying discarded hearts is telling these scientists even more.

In a recent series of studies, Penn researchers have explored a phenomenon that seems to be present regardless of what caused the patient's heart to fail: its individual cells are simply too stiff. What's more, the team has a promising strategy to get these stiff cells to regain some of their original elasticity.

"The heart cells you have when you're 10 or 20 are the heart cells you have when you're 80," said Ben Prosser, an assistant professor of physiology at Penn's Perelman School of Medicine. "These things have to beat every day of your life without fail."

Yet fail they do, and the problem is growing. In an aging, frequently overweight population, heart failure is the epidemic of our times, contributing to more than 300,000 deaths in the United States each year — twice the number claimed by lung cancer. The annual cost of treating heart failure is $18 billion — on par with the gross domestic product of Iceland — and it is projected to more than double by 2035, the American Heart Association says.

Symptoms can be alleviated with a variety of medicines, but doctors can do little to reverse the underlying disease — defined as a failure of the heart to pump enough blood — leaving the patient fatigued and out of breath.

Prosser and colleague Ken Margulies, a transplant cardiologist and professor at Penn, have high hopes for their research at the level of the individual heart-muscle cell.

The human heart contains several billion of these cells in its left ventricle, beating in unison to pump blood to the rest of the body. As in other kinds of cells, each heart-muscle cell is crisscrossed by a network of filaments called microtubules — miniature roadways that are used to shuttle proteins and other cellular cargo.

But in patients with heart failure, the individual cells become gummed up with an unusually high number of microtubules, the Penn researchers have shown, and it is not clear why. These additional filaments also bind to, and stiffen, the pumping machinery in each cell — interfering with the heart's overall ability to contract and relax.

"They provide a honeylike, viscous resistance," Prosser said.

This insight into the miniature workings of a heart cell became possible only in recent years with a laser-aided technique called super-resolution imaging — an advance that won the Nobel Prize in chemistry in 2014.

On a microscope in Prosser's lab, these dense, meshlike filaments inside each heart cell look like a closeup of steel wool. The researchers can even capture the action on video, revealing a springlike buckling of the microtubules with each beat.

In the team's most recent paper, published in June in the journal Nature Medicine, the researchers showed they could reduce the stiffness of this meshlike network in the lab in two ways: either with a cancer drug called parthenolide or through a type of genetic modification that prevents the filaments from sticking.

These treatments were administered only in individual heart cells, and years of study would be needed before they could be tried on a human patient. Heart failure is a complex disease in which all sorts of biochemical processes have gone wrong — not just the abnormal increase in microtubules. Still, the Penn team was encouraged that both of its experimental treatments strengthened and sped up the contraction of heart muscle cells by as much as 50 percent.

"If you could get back 40 to 50 percent, that's the difference between living and dying," Prosser said.

Elsewhere, researchers have sought to repair damaged hearts by using stem cells to grow new tissue, an effort that so far has met with little success. The Penn approach, on the other hand, would restore function to the heart cells that are already there.

The research by Prosser and Margulies drew praise from Steven R. Houser, director of the Cardiovascular Research Center at Temple University's Lewis Katz School of Medicine.

"I think this is certainly something worth trying," said Houser, past president of the American Heart Association. "They've identified a potential new way to make the failing heart beat better."

None of it would be possible without the donated hearts, said Margulies, the Penn cardiologist, who has amassed a database of tissue from more than 800 donors — starting in 1994, when he was at Temple.

That includes the old, diseased hearts from transplant recipients, which otherwise would be discarded. It also includes relatively healthy hearts from deceased organ donors, used as research controls. These organs are not suitable for transplant for one reason or another, such as a valve problem. But so long as their muscle cells are normal, they are invaluable as points of comparison with organs damaged by heart failure, Margulies said.

The donations are arranged by Gift of Life, the nonprofit organ-procurement organization that serves eastern Pennsylvania, South Jersey, and Delaware — obtaining consent from families and distributing the organs to hospitals.

Members of Margulies' and Prosser's labs are notified when a heart is available for research purposes, ready to come in at any hour of the day or night to prepare it for study — using enzymes and other chemicals to break it down into individual cells.

Among other tests, the researchers can measure the elasticity of a heart-muscle cell by putting it on a miniature, motorized stretcher — a device that Prosser developed when he was a postdoctoral researcher. Each end of the cell is attached to a glass holder, secured inside a laser-etched cavity.

"We grab it on either end, and we coat these cell-holders with biological glue," Prosser said.

Depending on the disease, the cells may have weak contractions, as measured by how much they shorten with each beat. Others may have relatively strong contractions, but they relax too slowly afterward. Multiply that effect over a few billion muscle cells, and the entire left ventricle becomes stiff and unable to fill up with blood. Adequate pumping strength, but not enough oxygenated blood to pump is an increasingly common form of heart failure that is tied to obesity, high blood pressure, and aging.

Several classes of drugs are available to reduce the burden in a heart that beats weakly. But for stiff hearts, no medicines have proven effective, Margulies said.

"It's been a tough nut to crack," Margulies said.

With 300,000 U.S. deaths a year from heart failure, few causes could be described as more urgent.