Editors note: High resolution images of amyloid clusters are available upon request to the release contact. |
CINCINNATI - Researchers at Cincinnati Children's Hospital Medical Center have linked the toxic protein clusters called beta-amyloids, known to be associated with Alzheimer's disease, to heart disease. The new discovery is both surprising and intriguing and could prove helpful in unraveling some of the mysteries surrounding heart disease, researchers say.
"When the heart of a patient with Alzheimer's disease starts failing, most people assume that it is the normal course of the disease. Now we know that the general pathological processes that can occur during Alzheimer's disease, may also occur in the heart and may be directly linked to heart disease, specifically, cardiomyopathy," said Jeffrey Robbins, Ph.D., director of the Division of Molecular Cardiovascular Biology at Cincinnati Children's and senior author of the study that appears in the June 21-25 online early edition of the Proceedings of the National Academy of Sciences (PNAS).
Cardiomyopathy occurs when the heart becomes enlarged or the walls of the heart's pumping chambers thicken, thereby restricting blood flow. The condition can leave the heart muscles weak and unable to pump blood efficiently. Although a number of genes have been linked to cardiomyopathy, scientists do not yet fully understand the pathological process that leads to heart failure.
Previous studies have shown that a mutation in a protein called alpha-B-crystallin, or CryAB, is directly linked to a cardiomyopathy known as desmin-related cardiomyopathy. These findings were replicated in the Robbins' lab in mouse models. As suspected, the mutated protein led to heart failure in the mice. But in this study, Robbins discovered that the diseased protein also formed protein clusters inside the cardiomyocytes (cells of the heart) and in doing so, interfered with heart function.
These particular protein clusters, also called aggregates, bore striking similarities to beta-amyloids: insoluble toxic protein clusters that form in the brains of Alzheimer's patients. Beta-amyloids are found inside and outside of cells and while they can be made of different proteins, carbohydrates and polysaccharides, they share common characteristics. In Alzheimer's patients, beta-amyloids occur when proteins don't fold correctly (sometimes called misfolding). They form plaques, or clusters of degenerative nerve endings and dendrites, which kills brain cells in Alzheimer's patients.
Robbins then looked to see whether these beta-amyloids were also present in cardiomyocytes taken from heart failure patients.
"Not only are beta-amyloids present in the cardiomyocytes from our animal models, but when you look across a spectrum of human heart failure patients, they are there at high concentrations in those cardiomyocytes as well," Robbins said. "The surprising thing is, I don't think anyone really expected to find toxic beta-amyloids inside of cardiomyocytes."
Prior to this study, beta-amyloids in the heart were thought to form outside of the cardiomyocytes and occurred because of an infection or other disease. The Robbins' study shows beta-amyloids are clearly present inside of the cardiomyocytes and thus, could interfere with the ability of the heart to function effectively as a pump. Follow-up studies will explore the significance of these findings.
"I think we will find that when the cardiomyocyte is under prolonged stress, it attempts to manage the stress by activating a process called the 'unfolded protein response,' which maintains normal cellular function by getting rid of defective proteins that don't fold correctly. If that process is compromised, or simply overwhelmed, you are going to get into trouble and beta-amyloids will form," Robbins said.
In Alzheimer's disease, beta-amyloids can build up in the brain for as long as 20 years before symptoms appear. Among the next steps for the Robbins' lab is exploring whether this is true of desmin-related cardiomyopathy as well.
"Now, what does the presence of beta-amyloids in the cardiomyocite mean? If you prevent it, will that lessen the severity of the disease? Does it have the potential to become a therapeutic target? At this point, does heart failure become reversible or not?" he said. These are among the questions Robbins will attempt to answer in follow-up studies.
This study was funded by the National Institutes of Health and the American Heart Association.
Cincinnati Children's Hospital Medical Center is a 423-bed institution devoted to bringing the world the joy of healthier kids. Cincinnati Children's is dedicated to transforming the way health care is delivered by providing care that is timely, efficient, effective, patient-centered, equitable and safe. It ranks third nationally among all pediatric centers in research grants from the National Institutes of Health. The Cincinnati Children's vision is to be the leader in improving child health. Additional information can be found at www.cincinnatichildrens.org.
Journal
Proceedings of the National Academy of Sciences