Cardiac Regeneration Research at the The Kühn Lab

The Kühn Lab — led by Bernhard Kühn, MD, and part of the Richard King Mellon Institute for Pediatric Research at UPMC Children’s Hospital of Pittsburgh — coordinates efforts with the Heart Institute and the McGowan Institute for Regenerative Medicine to advance its work from the research lab to clinical care.

Specialized contractile cells, called cardiomyocytes, are exceptional in that they lack the ability to replicate and proliferate, processes that are necessary to repair tissue damage and restore normal function. The innovative work at the Kühn Lab has already provided insight into the growth mechanisms of cardiomyocytes. The Kühn Lab’s long-term goal is to regenerate human hearts. This involves developing therapies that can help the heart muscle, the myocardium, to heal itself — to recover from a heart attack or restore a congenital heart defect to normal cardiac function — without surgery.

By focusing on the mechanisms of growth and regeneration of the myocardium, Dr. Kühn and his team’s research has already led to important discoveries. His work has shown that administration of two naturally occurring peptides, periostin and neuregulin, can stimulate cardiomyocytes to proliferate and, in animals, repair myocardial defects and restore cardiac function.

The Kühn Lab’s research team are focused on three main areas:

• Inducing Cardiomyocyte Proliferation
• Mechanisms of Myocardial Growth and Regeneration
• Translational Research 

The team is taking their findings to develop new and novel therapies for healing the hearts of both children and adults.

This includes a clinical trial that launched in December 2022 investigating the use of the beta-blocker, propranolol, to treat Tetralogy of Fallot.

Tetralogy of Fallot Clinical Trial – Propranolol and Cardiomyocyte Division

Congenital heart disease (CHD) is the most frequently occurring birth defect and a leading cause of heart failure. Prior research has shown that the heart muscle's ability to regenerate cardiomyocytes after birth remains intact in a person’s 20s, but this ability for regeneration lessens over time, particularly in patients with CHD and specifically those with Tetralogy of Fallot. The mechanisms by which this occurs suggest that hyperactive β-adrenergic receptor signaling suppresses the proliferation of cardiomyocytes in the setting of TOF.

Dr. Kühn’s lab in prior studies have shown that the beta-blocker, propranolol, shows promise for promoting cardiomyocyte regeneration in TOF models by tamping down the β-adrenergic signaling pathway.

To test the efficacy of propranolol on improving cardiomyocyte division, Dr. Kühn and colleagues devised and launched a single-center clinical trial at UPMC Children’s testing the drug in patients with TOF beginning at 1 month of age and continuing until the individual undergoes surgical repair for their condition, typically between three and 9 months of age.

Dr. Kühn’s study team devised a technique using thymidine tagged with a stable isotope (15N-thymidine). When cardiomyocyte cells multiply, they incorporate this tagged thymidine into their DNA. Using Multi-isotope Imaging Mass Spectrometry (MIMS), Dr. Kühn and colleagues can visualize this process and quantify cardiomyocyte division.

In addition to the study’s primary outcome measure of cardiomyocyte proliferation, the study is powered to assess the impact of propranolol on the heart's size and morphology using echocardiography and cardiac MR.

More details of the trail are available on ClincialTrials.gov (NCT04713657).