Abstract 13490: Cardiac Progenitor Cell Therapy in Right Heart Failure With Preserved Ejection Fraction

Abstract

Background: Hear failure with preserved ejection fraction (HFpEF) is a heterogeneous syndrome characterized by normal EF with abnormal relaxation. Although the significance of HFpEF in right ventricle (RV) remains elusive as well as cell therapy responses in HFpEF patients with single ventricular heart diseases (SHD) have not yet clarified. Purpose: We investigated the underlying mechanisms and potential benefits of cardiosphere-derived cell (CDC) therapy in HFpEF includes rat models and human SHD. Methods: Pulmonary artery banding (PAB) was created in rats for 4 weeks as RV failure models. In human study, 40 patients, aged 2.2±1.4 years, 91% diagnosed as RV type SHD, were analyzed. Both rat and human studies were defined as follows (HFpEF; EF≧40%, HFrEF; EF<40%), and intracoronary CDC infusion responses were assessed. Results: Rats received PAB showed RV dysfunction with significant cardiac fibrosis those were addressed by increased expression of heart failure or fibrosis related genes in both HFpEF and HFrEF rats rather than controls. CDC infusion led to marked increase in EF in rats with HFrEF but not HFpEF. Although CDC infusion did not augment EF in HFpEF, this treatment significantly decreased interstitial fibrosis and improved myocardial elastance in both HFpEF and HFrEF compared with baseline. Furthermore, CDC treatment markedly reduced Col1, Col3, NPPA and MMP2 expressions in both groups, whereas inflammatory cytokine such as Ccl2 and IL6 decreased only in HFrEF. Notably, CDC infusion did not affect the expression of MMP9, TIMP1 and TIMP2 in both groups. In human study, there was no difference in the incidence of late gadolinium enhancement detected by cMRI in two groups (20% in HFrEF and 15% in HFpEF); however, HFrEF but not HFpEF patients demonstrated a marked improvement in EF and reduced ventricular volumes and mass one year after CDC infusion. In contrast, the beneficial effects of CDC therapy could be observed by improved myocardial strain, elastance, and diastolic function in both groups. Conclusions: Our translational and clinical research of HFpEF in RV suggests that CDC infusion may have significant impact on diastolic relaxation and myocardial stiffening improvements to reverse ventricular fibrosis and remodeling leading to RV failure.