Beta-blocker Administration for Cardiomyocyte Division

• N-thymidine (Other), also known as Thymidine: 15N-thymidine will be administered to patients in order to quantify cardiomyocyte proliferation. 15N-thymidine will be administered as 5 separate syringes. Each syringe will contain the recommended daily dose based on participants weight. Subjects will be given the labeled thymidine by mouth once a day for 5 consecutive days. The dosing will begin one week after starting the study drug.The caregiver (parent or nurse) will administer the labeled thymidine by mouth via a syringe once a day for 5 consecutive days. They will be provided with a diary to keep track of study drug dosing.
• Urine Collection (Other): Parents will be asked to keep a diary of the child's feeding and diaper changes during the administration of thymidine. To monitor how the labeled thymidine is processed in the body, investigators will analyze urine from the child's diapers. Each time a diaper is changed, a cotton ball will be placed in the diaper. At the next diaper change, this cotton ball will be removed from the diaper, placed in a Ziploc bag, and stored in the freezer. They will be collected and stored cotton balls starting with the first administration of thymidine until 24 hours after the last administration. The frozen cotton balls may be collected from the home by a nurse or brought by parent to the next clinic visit.
• Echocardiogram (Procedure): On Study Day 1 to obtain baseline assessment of cardiac size. A second research dedicated echocardiogram will be done after being anesthetized for surgery. Echocardiography is routinely performed to determine right ventricle (RV) structure of the heart and function in Tetrology of Fallot/ Pulmonary Stenosis (ToF/PS) and is non-invasive.
• Cardiac MRI (CMR) (Procedure): A limited study protocol will be performed using the feed-and-bundle technique at the time of study enrollment, The feed and bundle technique is utilized so that the infant will be as comfortable as possible and asleep during the procedure. This is done to prevent the risk of sedation and allow for a more natural sleep. The baby is undressed, prepared with ECG-leads and an oxygen saturation probe, and fed. With this "feed, swaddle, and sleep" technique, scanning times of 30-60 minutes can be achieved, which provides the stillness needed for accurate visualization of the heart. A second CMR, with the same limited study protocol, will be performed under general anesthesia prior to surgical repair. It does not pose any risk of radiation exposure and will not require IV placement or contrast administration for a limited assessement of the right ventricle.
• Propranolol Hydrochloride (Drug), also known as Propranolol: For patients who are randomized to receive propranolol, The target dose for this study will be 3 mg/kg/day divided in 3 doses. The first dose will be given in the Pediatric Clinical and Translational Research Center (PCTRC) at 1mg/kg. Parents will administer propranolol (1 mg/kg po x 3 doses per day). Parents will be instructed to administer propranolol with feeding or soon after feeding, but not before feeding. families will also be given instructions for regarding 15N-thymidine dosing frequency and interval and provided with a log sheet to record administered and missed doses of propranolol and 15N-thymidine.
• Placebo (Drug): For patients who are randomized to receive placebo, the first dose will be given in the Pediatric Translational Research Center (PCTRC) and will be based on the patients weight. Parents will administer placebo 3 doses per day. Treatment with placebo will begin at 1 month of age and continue until 4 months of age or 24hrs prior to surgical repair, whichever comes first.
• Physical Exam (Procedure): On Study Day 1; monthly until surgery in conjunction with patient's clinical cardiology appointment; and at the time of surgery. Will include vital signs.
• Specimen Collection (Other): On the morning of surgery, after IV access is obtained for anesthesia 2 ml of blood will be collected for analysis. A small piece of heart tissue and fat that has already been removed during surgery will be collected for analysis.

Primary outcomes

• Cardiomyocyte Division [At the time of complete surgical repair, at approximately 3-9 months old, it is expected that a piece of RV myocardium will be resected. This tissue will be collected and analyzed using a multiple isotope mass spectrometer.]: To quantify cardiomyocyte division, investigators will utilize previously established MIMS (membrane introduction mass spectrometry) approach. Briefly, investigators will administer 5 enteral doses of 15N-thymidine to all patients at 1 month after birth. Cardiomyocytes that have undergone DNA replication after the intake of 15N-thymidine will incorporate the stable isotope into their DNA.

Secondary outcomes

• Hypertrophy as assessed by echocardiography [At 1 month and at time of surgery]: Analysis of the impact of propranolol on Right Ventricle Myocardial Volume
• Hypertrophy as assessed by Cardiac MRI [At 1 month and at time of surgery]: Analysis of the impact of propranolol on Right Ventricle Myocardial Volume
• Hypertrophy assessed by microscopy [At time of Surgery]: Analysis of the impact of propranolol on cardiomyocytes cross sectional area

Sex: All, ages: 30 Days to 100 Days

Inclusion Criteria:

* Male and female infants < 100 days of age with a diagnosis of tetralogy of Fallot (ToF) with pulmonary stenosis (PS) or double outlet right ventricle (DORV), tetralogy type by echocardiogram, who weigh greater than 2 kg at the time of consent and are tolerating enteral feeds.
* DORV variant

Exclusion Criteria:

* congenital atrio-ventricular block on EKG (PR interval > 120 ms),
* concomitant medication administration that interacts with propranolol,
* patient family is, in the opinion of the investigator, unable to comply with the requirements of the study protocol or is unsuitable for the study for any reason,
* Premature infants with corrected age < 5 weeks,
* asthma or underlying respiratory disease,
* presence of metal implants in infants.

• Results publication: El Khoudary SR, Fabio A, Yester JW, Steinhauser ML, Christopher AB, Gyngard F, Adams PS, Morell VO, Viegas M, Da Silva JP, Da Silva LF, Castro-Medina M, McCormick A, Reyes-Mugica M, Barlas M, Liu H, Thomas D, Ammanamanchi N, Sada R, Cuda M, Hartigan E, Groscost DK, Kuhn B. Design and rationale of a clinical trial to increase cardiomyocyte division in infants with tetralogy of Fallot. Int J Cardiol. 2021 Sep 15;339:36-42. doi: 10.1016/j.ijcard.2021.07.020. Epub 2021 Jul 12. PMID 34265312

• Bernhard Kuhn, MD, Principal investigator, Weill Medical College of Cornell University

NIH grants: R01HL155597