Safety and feasibility of adjunct autologous cord blood stem cell therapy during the Norwood heart operation

Abstract

Background: We conducted this phase I, open-label safety and feasibility trial of autologous cord blood (CB) stem cell (CBSC) therapy via a novel blood cardioplegia-based intracoronary infusion technique during the Norwood procedure in neonates with an antenatal diagnosis of hypoplastic left heart syndrome (HLHS). CBSC therapy may support early cardiac remodeling with enhancement of right ventricle (RV) function during the critical interstage period.

Methods: Clinical grade CB mononucleated cells (CBMNCs) were processed to NetCord-FACT International Standards. To maximize yield, CBSCs were not isolated from CBMNCs. CBMNCs were stored at 4 °C (no cryopreservation) for use within 3 days and delivered after each cardioplegia dose (4 × 15 mL).

Results: Of 16 patients with antenatal diagnosis, 13 were recruited; of these 13 patients, 3 were not treated due to placental abruption (n = 1) or conditions delaying the Norwood for >4 days (n = 2) and 10 received 644.9 ± 134 × 10⁶ CBMNCs, representing 1.5 ± 1.1 × 10⁶ (CD34⁺) CBSCs. Interstage mortality was 30% (n = 3; on days 7, 25, and 62). None of the 36 serious adverse events (53% linked to 3 deaths) were related to CBMNC therapy. Cardiac magnetic resonance imaging before stage 2 (n = 5) found an RV mass index comparable to that in an exact-matched historical cohort (n = 22), with a mean RV ejection fraction of 66.2 ± 4.5% and mean indexed stroke volume of 47.4 ± 6.2 mL/m² versus 53.5 ± 11.6% and 37.2 ± 10.3 mL/m², respectively. All 7 survivors completed stage 2 and are alive with normal RV function (6 with ≤mild and 1 with moderate tricuspid regurgitation).

Conclusions: This trial demonstrated that autologous CBMNCs delivered in large numbers without prior cryopreservation via a novel intracoronary infusion technique at cardioplegic arrest during Norwood palliation on days 2 to 3 of life is feasible and safe.

Trial registration: ClinicalTrials.gov NCT03431480.

Keywords: Norwood procedure; cell therapy; cell transplantation; congenital heart disease; hypoplastic left heart syndrome; pediatric cardiopulmonary bypass surgery; phase I trial; umbilical cord blood stem cells.