The heart is a pump that wears out over time—that, at least, was the prevailing view. New research has shown that the heart’s aging results from changes in intercellular communications, which tell heart cells, sometimes even healthy ones, to stiffen and break down.
By decoding these complex messages, a team of researchers, led by Pinar Zorlutuna, the Roth-Gibson Professor of Bioengineering at the University of Notre Dame, including the study’s first author, doctoral student in Notre Dame’s Bioengineering Graduate Program George Ronan Jr., along with fellow doctoral students Frank Ketchum and Lauren Hawthorne, has shown that the inevitable aging of the heart could be interrupted and perhaps even reversed. Their results were published in Biomaterials.
Central to the team’s research was a revolutionary ‘heart-on-a-chip’ device, featuring interwoven channels that allow researchers to grow healthy and damaged heart tissues side-by-side.
“This postage-stamp size piece of technology allows us to experiment on human heart cells in a highly controllable way,” said Zorlutuna. “We can simulate diseases and therapies with a great degree of accuracy without involving human patients.”
To understand how the heart ages, the team compared extracellular vesicles (EVs)—nanoparticles excreted by cells—from the heart and blood of young and old people, half from men and half from women. While scientists used to think of EVs as part of the body’s waste disposal system, they now recognize them as a sophisticated postal system, delivering messages that trigger biological functions.
Zorlutuna’s team found that EVs stored in the tissue surrounding the heart played a paradoxical role—keeping the heart strong and healthy in youth but causing stiffening and scarring in later years. This happened because vesicles in young hearts delivered a constant supply of chemical cocktails that replenished cells with protective gene regulators (miRNAs). Aging hearts, on the other hand, were flooded with EVs carrying proteins that triggered inflammation and disease.
Once they had succeeded in modeling heart stiffening and scarring on the device—a typical byproduct of aging—the team simulated stress from a heart attack and hypertension by depriving the cells of oxygen and normal blood flow. This resulted in increasing the scarring of the heart tissue by five and 10 times respectively. The team then turned to a critical question: Could they repair it?
The team used tiny fat-based bubbles called Lipid Nanoparticles (LNPs), the same technology used to deliver the COVID-19 vaccines, to deliver the chemical cocktail of gene regulators young hearts produce. The treatment was a success: the treated chips had 50 percent more living cells than the untreated ones, and the scarring was cut in half.
“The study is the first to deliver a potential treatment with a lipid nanoparticle and test it on a heart-on-a-chip,” said Zorlutuna. “In the future, we might be able to measure these specific markers in a patient’s blood to get a highly accurate reading of how fast their heart is aging. The ability to model heart disease in such a life-like manner also opens up exciting possibilities for enhancing drug development for many chronic cardiovascular diseases.”
Funding for this research was received from the National Science Foundation and National Institute of Health.
—Karla Cruise, Notre Dame Engineering. Photos not otherwise credited by Wes Evard, Notre Dame Engineering