Abstract 19759: Improvement of Diastolic Function by Exosome Injection in a Rat Model of Heart Failure With Preserved Ejection Fraction
Introduction: Cardiosphere-derived cells (CDCs) improve diastolic function when injected in rats with heart failure with preserved ejection fraction (HFpEF) by decreasing inflammation and fibrosis. Here we sought to determine if CDC exosomes (CDCexo) can improve diastolic function in a rat model of HFpEF.
Methods: Dahl salt-sensitive (DS) rats (n=30) were fed a high-salt diet (8% NaCl) to induce HFpEF from 7 weeks of age. DS rats fed a normal-salt diet (n=13) served as controls. At 14 weeks of age, systolic and diastolic function parameters were measured using transthoracic echocardiogram (ECHO) to verify diastolic dysfunction. CDCexo (300-400 ug of protein, isolated from serum-free media conditioned by human CDCs) were delivered through direct intra-myocardial injections to HFpEF rats (n=19). HFpEF rats (n=11) injected with phosphate buffered saline (PBS) served as controls. Animals were followed until 18 weeks of age with ECHO.
Results: At 14 weeks of age, diastolic dysfunction in high-salt rats was confirmed by decreased E/A ratio (1.26±0.20 vs. 1.56±0.13, p<0.001) and increased E/E’ ratio (16.82±2.54 vs. 13.53±1.87, p<0.001) compared to normal-salt rats. Ejection fraction (EF) did not differ (67.30± 3.96 vs. 69.74± 4.04, p=0.075) in the two groups. Four weeks after treatment, repeated ECHO revealed normalized E/A ratio both in the CDCexo and PBS groups (E/A ratio 1.57±0.16 vs. 1.46±0.17, p=0.189). However E/E’ ratio was decreased in the CDCexo group compared to PBS controls (E/E’ ratio 15.62±0.93 vs. 19.71±4.25, p=0.031), indicating reversal of diastolic dysfunction after CDCexo treatment. Survival analysis showed a trend towards decreased mortality in the CDCexo group (4/17=23.5% vs. 4/9=44.4%) compared to PBS group.
Conclusions: Exosomes isolated from human CDCs mimic the functional benefits of CDCs in a rat model with HFpEF by reversing diastolic dysfunction. Unlike xenogeneic CDCs, which are rapidly cleared and are ineffective in immunocompetent animals, human CDCexo fully mimicked the benefits previously seen with species-matched CDCs in this model of HFpEF. Given that CDCexo are known to confer anti-inflammatory and anti-fibrotic effects, the present data support the concept that exosomes mediate the benefits of CDCs in HFpEF.
Author Disclosures: J. Cho: None. R. Gallet: None. G. de Couto: None. L. Sanchez: None. E. Marbán: Ownership Interest; Significant; Capricor Therapeutics, Inc.. Consultant/Advisory Board; Significant; Capricor Therapeutics, Inc.. E. Cingolani: None.
- © 2016 by American Heart Association, Inc.