Cardiomyocyte Regeneration Research Featured in New England Journal of Medicine
January 21, 2020
Research from the laboratory of Bernhard Kühn, MD
, associate professor of pediatrics and director of the Pediatric Institute for Heart Regeneration and Therapeutics at UPMC Children’s Hospital of Pittsburgh recently was featured in a January clinical implications of basic research editorial
in the New England Journal of Medicine
Dr. Kühn and colleagues research on the use of beta-blockers
to supplement surgery to repair a form of congenital heart disease (CHD) known as Tetralogy of Fallot was published in October 2019 in the journal Science Translational Medicine
. They showed that administering the beta-blocker propranolol could promote regeneration of infant heart muscle and potentially mitigate the lasting effects of CHD.
Dr Kühn’s team collected heart tissue from 12 infants who underwent corrective surgery for Tetralogy of Fallot, and found that more than half of the cardiomyocytes in these samples had started to divide but could not complete the process. The ultimate result was fewer cardiomyocytes overall, which makes the heart more vulnerable to damage in the future.
Through a series of experiments in human and murine tissue, the researchers traced this cell division failure back to β-adrenergic receptors. The natural next step was to ask whether the β-adrenergic receptor blocker propranolol could stimulate proper cell division in infants with congenital heart defects and improve heart function.
Indeed, in the heart tissue samples taken from infants with Tetralogy of Fallot, propranolol enabled dividing cells to separate properly. In mice, propranolol treatment during the first weeks of life allowed for better recovery from heart attacks in adulthood. Compared to untreated controls, mice who were given propranolol as pups retained 30% more cardiomyocytes and were able to eject 24% greater blood volume following a heart attack.
According to Dr. Kühn, having such promising results with a tried-and-true drug like propranolol means the pathway to clinical translation could be relatively quick. “This all comes together in a very applicable way,” says Dr. Kühn. “Propranolol was synthesized nearly 60 years ago, so we’re able to bypass a lot of the ground work that would have to be done if we had identified a receptor that doesn’t already have a drug for it.”
On the basis of their findings in the Science Translational Medicine paper, Dr. Kühn and colleagues are now developing applications for R01 funding and institutional review board (IRB) and investigational new drug (IND) proposals to expand and continue their promising beta-blocker and CHD studies.
Kühn lab research group (L to R): Honghai Liu, PhD; Jocelyn Basso; Lu Han, PhD; Niyatie Ammanamanchi, MS; Bernhard Kühn, MD.