Intramyocardial cell-based therapy during bidirectional cavopulmonary anastomosis for hypoplastic left heart syndrome: The ELPIS phase I trial

BackgroundHypoplastic left heart syndrome (HLHS) survival relies on surgical reconstruction for the right ventricle (RV) to provide systemic circulation. This leads to substantially increased loads on the RV, wall stress, maladaptive remodeling and dysfunction, which in turn can increase risk of death or transplantation. ObjectivesWe conducted a phase I multicenter trial to assess safety and feasibility of intra-operative MSC injection in HLHS patients to boost RV performance in the systemic position. MethodsAllogeneic MSCs were directly administered by intramyocardial injections during the second stage palliative operation. The primary endpoint was safety. ResultsTen patients received intramyocardial injections of allogeneic MSCs (Lomecel-B). No patients experienced major adverse cardiac events (MACE). All subjects were alive and transplant-free at 1 year following, and experienced growth comparable to healthy control historical data. Cardiac magnetic resonance imaging (CMR) revealed improving tricuspid regurgitant fraction (Baseline: 0.45{+/-}0.19; 6 mo.: 0.32{+/-}0.06; 12 mo.: 0.06{+/-}0.09), while global longitudinal strain (Baseline: -24.39{+/-}6.99; 6 mo.: -20.55{+/-}3.05, p > 0.05 vs baseline; 12 mo.: - 23.88{+/-}4.6, p>0.05 vs baseline) and RV ejection fraction (EF; baseline: 62.62{+/-}5.99; 6 mo.: 53.69{+/-}9.56; 12 mo.: 52.31{+/-}5.63: p=NS for change over time) were unchanged. Computational modeling identified 167 derived RNAs specific to circulating exosomes originating from transplanted MSCs corresponding to RVEF changes and identifying potential mechanistic underpinnings. ConclusionsIntramyocardial MSCs appear safe in HLHS patients, and may favorably affect RV performance. Circulating exosomes of transplanted MSC-specific provide novel insight into bioactivity. Conduct of a controlled phase trial is warranted and is underway. Condensed AbstractThe ELPIS phase I trial was designed to assess safety and feasibility of intramyocardial injection of allogeneic MSCs into the RV during second stage palliation of HLHS. There were no incidences of major adverse cardiac events (MACE) or other safety concerns, and there was a 100% transplant-free survival at 1-year follow-up, supporting the safety and feasibility of this approach. The ELPIS results are important for advancing MSC therapy for all ages and congenital heart conditions, and warrant further investigation in a controlled Phase II trial powered for efficacy.