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August 8, 2017

Fooling the Heart to Be Healthier

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    The far right image shows how a cardiotrophin treatment repaired heart muscle after a heart attack in a rat model. The blue areas are scar tissue and the red sections are healthy heart muscle. [Cell Research]

    They say that hope deferred makes the heart sick. Well, those that have suffered heart attacks just got some good news that may afford them some new optimism and lead toward improved cardiac health. A team of investigators from The Ottawa Hospital, the University of Ottawa, the University of Ottawa Heart Institute, and Carleton University have discovered that a protein called cardiotrophin 1 (CT1) can trick the heart into growing in a healthy way and pumping more blood, just as it does in response to exercise and pregnancy. Findings from the new study—published online today in Cell Research in an article entitled “Cardiotrophin 1 Stimulates Beneficial Myogenic and Vascular Remodeling of the Heart”— shows that this kind of heart growth is very different from the harmful enlargement of the heart that occurs during heart failure.

    "When part of the heart dies, the remaining muscles try to adapt by getting bigger, but this happens in a dysfunctional way, and it doesn't actually help the heart pump more blood," explained senior study investigator Lynn Megeney, Ph.D., professor at the University of Ottawa and senior scientist at The Ottawa Hospital. "We found that CT1 causes heart muscles to grow in a healthier way and it also stimulates blood vessel growth in the heart. This actually increases the heart's ability to pump blood, just like what you would see with exercise and pregnancy."

    Cardiovascular disease is a leading cause of death and disability in high-income countries and a growing problem around the world. Cardiac hypertrophy (heart muscle growth) is the typical compensatory response to heart abnormalities and damage. While hypertrophy can sometimes be beneficial, in pathological cases the heart muscle mass increases (wall thickness) without a corresponding improvement in cardiac function. This form of hypertrophy often leads to heart failure, which occurs when the heart can't pump enough blood through the body, often because a heart attack has damaged the heart muscle tissue.

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    Cardiotrophin 1 stimulates a good kind of heart muscle growth, generating long healthy fibers (right panel). Heart disease causes an unhealthy kind of heart muscle growth, similar to what is seen with phenylephrine treatment (middle panel). [Cell Research]

    In the current study, the researchers conducted a variety of studies in mice, rats, and cells growing in the lab. In addition to CT1, some of the studies involved a drug called phenylephrine (PE), which is known to cause heart growth similar to what is observed in pathological cardiac hypertrophy.

    “We identified the cytokine cardiotrophin 1 (CT1) as a factor capable of recapitulating the key features of physiologic growth of the heart including transient and reversible hypertrophy of the myocardium, and stimulation of cardiomyocyte-derived angiogenic signals leading to increased vascularity,” the authors wrote. “The capacity of CT1 to induce physiologic hypertrophy originates from a CK2 [casein kinase 2]-mediated restraining of caspase activation, preventing the transition to unrestrained pathologic growth.”

    Specifically, the researchers noted that heart muscle cells treated with CT1 became longer, healthier fibers, while those treated with PE just grew wider. Moreover, the scientists noticed that CT1 causes blood vessels to grow alongside the new heart muscle tissue and increases the heart's ability to pump blood. Finally, the research team showed that when CT1 treatment stopped, the heart went back to its original condition, just like it does when exercise or pregnancy ends. Yet, the dysfunctional heart growth caused by PE is irreversible.

    "This experimental therapy is very exciting, particularly because it shows promise in treating both left and right heart failure," noted co-senior study investigator Duncan Stewart, M.D., a cardiologist and evp of research at The Ottawa Hospital. "Currently, the only treatment for right heart failure is a transplant. And although we have drugs that can reduce the symptoms of left heart failure, we can't fix the problem, and left heart failure often leads to right heart failure over time."

    The investigators were excited by their findings and are looking toward the future with the hope of developing partnerships to test this protein in patients. Interestingly, the researchers noted that while exercise could theoretically have the same benefits as CT1, people with heart failure are usually limited in their ability to exercise.  

    "An intriguing aspect of this research was how human CT1 was able to promote a healthy growth response in multiple animal models," concluded co-author Patrick Burgon, Ph.D., a scientist at the University of Ottawa Heart Institute and assistant professor at the University of Ottawa. "This suggests the action of CT1 is universally conserved and puts us much closer to therapy."

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