CCC and AHA 2014: Overcoming Challenges to Repair Heart Attack Damage

December 10, 2014

We know the best ways to prevent a heart attack. Healthy eating, being physically active and not smoking are key among them. And advances in cardiac care are helping people live longer and with a better quality of life if they do have a heart attack. But there is no way to repair the damage and scarring to the heart that many who survive a heart attack are left with. That damage can lead to heart failure, heart valve disease or life-threatening arrhythmias down the road.

Doctors and researchers want to find ways to actually repair the heart attack damage, not just salvage what healthy tissue is left. Regenerative medicine—harnessing the body's own stem cells to repair damaged heart tissue—has made promising advances toward this goal. We are learning more and more about how these cells work in the body and how they might be coaxed into action to repair or replace the large amount of tissue damaged by a heart attack, but some basic challenges remain.

Up to 1 per cent of the cells in a healthy heart naturally die and are replaced every year. The cells responsible for this repair work include two types of stem cells: cardiac progenitor cells (CPCs), which produce heart muscle, and endothelial progenitor cells (EPCs), which produce new blood vessels.

Two of the University of Ottawa Heart Institute researchers exploring the potential of these two cell types to heal a damaged heart are Erik Suuronen, PhD, Director of the Cardiovascular Tissue Engineering Laboratory, and Darryl Davis, MD, an electrophysiologist and Director of the Cardiac Translational Research Laboratory.

Both cell types have two abilities that make them of interest in regenerative medicine. First, they release hormones and other cell-signalling molecules that promote tissue repair. Second, they have the potential to engraft—"stick"—to the heart and actually produce new healthy tissue. In theory, a patient's own stem cells could be harvested, engineered to improve their repair abilities and injected back into the heart.

So far, scientists have had the most success harnessing the first trait, the body's own repair mechanism, in experiments, though the gains in heart function so far have been modest. "The gains we've seen with cardiac stem cells in early clinical trials have been based on their ability to produce healing hormones that promote the salvage of reversibly damaged tissue," explained Dr. Davis, whose lab was the first in Canada to culture cardiac stem cells.

Positron emission tomography imaging showing the presence of radiolabeled collagen matrix after injection into the injured heart muscle (indicated by the arrow).

His lab and Dr. Suuronen's presented a total of 17 abstracts at the Canadian Cardiovascular Congress (CCC) and American Heart Association Scientific Sessions this year. Many of these studies focused on better understanding which hormones released by stem cells are most vital to the healing process, and how to increase the expression of those hormones in cells for potential therapeutic use.

A study from the Davis lab showed that by engineering stem cells to produce a surplus of a hormone called SDF-1, which acts as a cellular distress call, the recruitment of stem cells to damaged heart tissue was enhanced. The researchers also found that by increasing the amount of another hormone, IGF-1, the number of stem cells that survived after injection into the heart was greater.

However, as important as cell signalling is to the repair process, explained Dr. Davis, "the basis for using these cells lies in their ability to engraft and grow into new working heart tissue. To go forward, we need to make them stick around and do what they're supposed to."

This has proven difficult. In previous studies from the Davis lab, only 10 per cent of cardiac stem cells injected into a damaged heart remain after an hour. A combination of the heart's mechanical turbulence and the toxic environment of the inflammatory response following a heart attack wreak havoc on the fragile stem cells. Both Drs. Suuronen and Davis are developing strategies to protect stem cells, to buy the cells the time they need to embed themselves into the heart.

Dr. Suuronen's lab has focused on injectible collagen-based biomaterials to repair damage to the heart's support structure, a complex matrix that stem cells rely on for both physical support and cell-to-cell communication via hormones and other proteins. These biomaterials may be able to protect cells already in the heart at the time of a heart attack, he explained, providing a more hospitable environment for stem cell therapy.

"If you know what's lacking in the environment of the heart, then you can reinforce that environment [with the needed molecules], so that when you deliver stem cells, they're better able to function," said Dr. Suuronen.

In one study presented at the conferences, his team showed that adding a protein called CCN1 to a collagen matrix improved repair of heart muscle compared to delivering the matrix alone. Another study showed that collagen matrix could reduce the amount of a signalling molecule that interferes with new blood vessel formation.

The Davis lab has been exploring encapsulating stem cells themselves in a protective coating. In one study, encapsulating cardiac stem cells in protective cocoons made of agarose and supportive proteins increased by threefold their engraftment into the heart.

The work from both labs has so far been conducted in animal models. A final hurdle to human trials of both CPCs and EPCs, explained Dr. Davis, is creating stem cell products free of foreign contaminants. His lab recently transitioned its cell culture manufacturing protocols over to the standards required for clinical trials. "That was really the last barrier we need to surmount. In the coming months, we'll be having preclinical trial application discussions with Health Canada to implement some of our technologies in the near future," concluded Dr. Davis.