How the Heart Hardens, Biologically

With age and injury, the soft tissues of the heart can turn to bone. Can this deadly process be reversed?

The Autopsy Heart
Take heart: researchers are probing how the hard-hearted get that way, and whether they can be turned back. "La autopsia," Enrique Simonet / Wikimedia Commons

In matters of the heart, a lot can go wrong. As we age, high blood pressure can overburden this tenacious muscle, causing stroke or heart failure. Smoking cigarettes may harm your heart and blood vessels, as well as damaging individual blood cells. Or the natural effects of old age can render the heart simply too weak to do its job, manifesting in tiredness, shortness of breath or even death. But the heart can also harden, its soft muscle changing into bone.

“The cardiovascular system is one soft tissue that gets calcified very easily,” said Arjun Deb, a heart researcher at the University of California at Los Angeles, referring to the accumulation of calcium salts in the tissues of the heart. This is a bad development: Calcification in blood vessels can eventually block them up, and in the heart, it can actually block the electric signals that keep the cardiac muscles beating. Normal aging, conditions such as kidney disease or diabetes, or even physical trauma to the chest can trigger heart calcificationbut the exact hardening mechanism is still largely unknown.

Now researchers have shed light on this enigmatic process by looking at individual cells to see exactly how the flexible tissues of the heart and blood vessels stiffen, impairing beating and circulation. In a study published yesterday in the journal Cell Stem Cell, Deb and his team sought to find out the cause for deadly heart calcification and how the process could potentially be stopped in its tracks. That would be heartening news. Calcification in the heart and blood vessels is one of the main factors in heart disease, which kills about 610,000 Americans annually, according to the Centers for Disease Control.

Armed with the knowledge that heart injury can often result in calcification, the researchers focused their efforts on fibroblasts, connective tissue cells that play an important role in healing wounds. After an injury, fibrocyte cells in the affected area are activated into fibroblasts, which generate connective tissue for healing. Some of these fibroblasts go awry in soft tissue and become like osteoblasts, the cells that produce bone in the skeletal system.

By genetically tagging the fibroblasts in lab mice and then causing various types of injuries to the animals, the researchers were able to see the nearby fibroblast cells turn into cells resembling osteoblasts. Scientists then took these transformed cells and transplanted them into the skin of healthy mice, where the mutant cells began calcifying the rodents’ skin within a month. When grown in lab dishes, harvested human fibroblast cells did the same thing. The mere presence of these osteoblast-type cells, it seemed, worked to calcify surrounding tissues.

This new understanding helped scientists identify a potential mechanism for preventing a fatal hardening of the heart from ever taking place. While studying these mutating fibroblasts, Deb and his team noticed that the cells started to overproduce a protein called ENPP1 in response to heart injury. When they injected an osteoporosis drug into the mice after injuries that usually resulted in heart calcification, not a single mouse developed heart hardening. The drug seemed to stymie the actions of ENPP1 and thus completely prevent calcification, Deb said.

Unfortunately, it seems that this treatment only works when used before the calcification takes place. This kind of preventative treatment would be impractical in humans, since it would be impossible to know when precisely heart damage takes place, says Dr. Paolo Raggi, academic director of the Mazankowski Alberta Heart Institute in Edmonton, Canada. Raggi, who was not involved in this study, also expressed caution at whether these results in mice would also work in humans.

Nevertheless, he said the researchers did “a fantastic job” at discovering a pathway for how heart calcification occurs. “It’s unbelievable the amount of work they did for one simple question,” Raggi says, noting that the pieces of evidence had been there previously, but that they had not yet been formed into “an elegant story.” “I think there’s definitely potential for future development into this particular field,” he adds.

Deb and his team are already looking ahead to see whether it might be possible not only to prevent, but to reverse a hardened heart. Their next goal is to find out how and why ENPP1 causes calcification after heart injury, in hopes that there might be a way to reverse the hardening. And since this same protein appears to also be involved in calcification in other soft tissues where it shouldn’t occur, Deb hopes that future research on this topic will one day lead to a treatment that can prevent and heal calcification in any part of the body.

“There is promise,” Deb says. In other words: Don't lose heart.

Correction, November 20, 2016: This post originally misstated the title of the journal Cell Stem Cell.

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