Effectiveness of combination allogeneic stem cells in a novel large animal

model of chronic kidney disease-induced heart failure with preserved

ejection fraction (HFpEF)

A.M. Castellanos, B.A. Tompkins, M. Natsumeda, V. Florea, K. Collon, J. Rodriguez, M.

Rosado, W. Balkan, J. Hare, I.H. Schulman. University of Miami Leonard M. Miller School
of Medicine, Interdisciplinary Stem Cell Institute, Miami,United States of America
Background: Chronic Kidney Disease (CKD) has been recognized as an independent risk
factor for cardiovascular morbidity and mortality. Left ventricular hypertrophy and HFpEF
are the primary manifestations of the cardio-renal syndrome, which is found in 60 to 80% of
CKD patients. Evidence-based therapies that improve morbidity and mortality in HFpEF are
lacking. HFpEF has been associated with endothelial dysfunction and activation of the renin-
angiotensin-aldosterone system. Stem cell therapy has been shown to reverse fibrosis,
increase neovascularization, and promote cardiac repair mainly through paracrine effects.
Purpose:We hypothesized that stem cell treatment ameliorates HFpEF in a CKD model.
Methods: Yorkshires pigs (n=27) underwent 5/6 nephrectomy via renal artery embolization
using PVA particles and ethanol. At baseline, 4 and 12 weeks postembolization, glomerular
filtration rate (GFR), creatinine, BUN, proteinuria, renal and cardiac MRI, and pressure
volume loops (PV loops) were obtained. Four weeks after embolization, pigs were
randomized into 4 groups (n=5 per group): MSC (10×106), c-kit (10×106), combination
group (MSC-c-kit: 1:1 ratio (10×106)), or placebo. Allogeneic cell therapy was delivered via
the patent renal artery in the remnant kidney. At 12 weeks the swine were euthanized.
Results: The CKD model was confirmed by an increased in creatinine and BUN and
decrease in GFR. Blood pressure was not different between baseline and 4 weeks post
embolization (p=0.7). HFpEF was demonstrated at 4 weeks by increase in left ventricular
(LV) mass of 20.3% (p=0.0001) and wall thickening (p<0.008), increase in end diastolic
pressure (p=0.01), end diastolic pressure volume relationship (p=0.005), and arterial elastance
(p=0.03), without a change in ejection fraction. Diffuse intramyocardial fibrosis was evident,
assessed by histological analysis and delayed enhancement MRI imaging. After 12 weeks, the
mean blood pressure was higher in the placebo group versus the cell treated groups. GFR
predominantly improved in the combination group (p=0.033). End diastolic volume increased
significantly in the placebo and c-kit (20.99±3.500ml p=0.009 and 12.64±2.09 p=0.004,
respectively) groups. End systolic volume increased most in the placebo group (7.14±1.62ml;
p=0.022). Ejection fraction, wall thickness, and LV mass did not differ between groups at 12
weeks.
Conclusion: A CKD large animal model manifests the characteristics of HFpEF, including
an increase in LV mass, wall thickening, fibrosis, and LV and arterial stiffness. Intra-renal
artery allogeneic cell therapy was safe. A beneficial effect of cell therapy was observed in the
combination and MSC groups. These findings have important implications on the use of cell
therapy for HFpEF and cardio-renal syndrome.

A.M. Castellanos B.A. Tompkins M. Natsumeda V. Florea K. Collon J.

Rodriguez M. RosadoW. Balkan J. Hare I.H. Schulman
European Heart Journal, Volume 38, Issue suppl_1, 1 August 2017,
ehx501.P586,https://doi.org/10.1093/eurheartj/ehx501.P586
Published:

29 August 2017