P4242Transcoronary cardiac progenitors in patients with functional single ventricle: two-year follow-up of the phase 1/2 clinical trials

Abstract

Background: Single ventricle physiology is a fatal congenital heart disease. Patients who have undergone a series of staged palliation remain at risk for the development of late‐onset heart failure. Cardiosphere‐derived cells (CDCs) have shown to reduce myocardial fibrosis and increase ventricular function in preclinical studies. Purpose: We aimed to assess safety and efficacy of intracoronary infusion of autologous CDCs in patients with single ventricle physiology. Methods: In the prospective, randomized phase 1/2 clinical trials, we enrolled 48 children (2.8±1.4 yr) with single ventricle physiology 4 weeks after surgical palliation between January, 2011, and March, 2015. For 24 patients assigned to receive CDCs, autologous CDCs (3.0×105 cells per kilogram of the body weight) were isolated from atrial tissue harvested during cardiac surgery and selectively infused into coronary arteries 4 weeks after staged palliation. Treatment arm was compared with 24 controls who received cardiac reconstruction alone. Among the control subjects, 17 participants received late CDC infusion upon request as an ethical consideration. The primary endpoint was to assess the safety and feasibility of such an approach in children and the efficacy endpoints were determined by the cardiac function improvement on MRI and reduction of heart failure status. Multiple linear regression analysis was performed to investigate the prognostic factors that may impact on cardiac function improvement. Results: There were no 30‐day treatment‐emergent serious adverse events and no patients had died or developed cardiac tumors by 2‐year observation. Forty‐one patients have received CDC infusion at final analysis. Compared with controls, CDC‐treated patients showed significantly improved cardiac function (P<0.01) and regional contractility as well as reduced myocardial fibrosis (P<0.01) measured by MRI. These clinical outcomes could be addressed by marked decrease in BNP levels (P<0.001) and reduction of ventricular stiffness (P<0.001) and heart failure status (P<0.001), resulting in reduced parenting stress at 2‐year compared with baseline. Although the therapeutic effects had specifically impact on patients with heart failure with reduced ejection fraction rather than those with preserved ejection function, CDC infusion substantially produced a marked improvement in regional contractile and diastolic functions in both types of heart failure. In multivariate prediction analysis, the ventricular function and weight for age z score at CDC infusion were identified as dominant variables to predict the functional improvement (P=0.001). Conclusion: In the phase 1/2 clinical trials, intracoronary infusion of autologous CDCs in 41 patients with functional single ventricle was feasible and safe and demonstrated a durable effect at 2‐year, manifested by significant improvement in ventricular function, heart failure status, and concordant outcomes of healthrelated quality of life.