This document discusses cell therapies for heart failure. It summarizes several studies that have shown cell therapies can improve left ventricular function after a myocardial infarction in animal models. However, the data is limited on whether cell therapies work in established heart failure models, on background medical therapy, or have durable effects. Several meta-analyses of clinical trials found moderate evidence cell therapies improve left ventricular ejection fraction but low quality evidence of potential benefits on mortality. Other studies found no effects on outcomes like death or left ventricular function compared to controls. Further studies directly examining human hearts found very poor engraftment of transplanted cells and no improvements in vascularity or fibrosis. In conclusion, while cell therapies show some modest benefits in animal models and clinical trials,

1. Cell Therapies in Heart Failure:
They don’t work!
Patient Selection and
Preoperative Considerations
Robb MacLellan, MD
Robert A. Bruce Chair in Cardiovascular Research
University of Washington Medical Center
University of Washington

2. Cell transplantation improves
LV function post-MI
Makkar et. al. J. Cardiovasc. Pharmacol. Ther. 10:225-33
Time (months)
-2 -1 0 1 2 3
Ejectionfraction(%)
36
40
44
48
52
56
60
64
Cell Tx
Control
n=4 n=3
n=10
n=5
n=8
n=8
n=10
n=10
*
Cell Transplantation
*
• Cell therapies have been
shown to beneficial after MI
in multiple animal species
with many cell types and
using diverse delivery
methods at multiple times
post-MI
• Very limited data that cell
therapies:
– Work in established HF models
– Work on a background of
appropriate medical therapy
– Are durable

3. • How strong is the data
supporting the cardiac
cell therapy in HF?
Promising Therapy or Great Potential?
• What are the effects of
cell transplantation in
human hearts?

4. Sadat, K et al, J Nucl Cardiol. 2013
Impact of bone marrow cell therapy on left
ventricular ejection fraction after MI (2013)

5. Cardiac cell therapy improves mortality in
patients with heart failure
Fisher SA et al, CircRes Online

6. Promising Therapy or Great Potential?
• Cochrane meta-analysis (2014)
– 23 Randomized clinical trial
– 1255 patients
• Results
– moderate quality evidence that BMSC treatment
improves LVEF.
– “some evidence for a potential beneficial clinical
effect in terms of mortality after at least one year
in people who suffer from chronic IHD and heart
failure, although the quality of evidence was low.”
Fisher SA et al, Cochrane Database Syst Rev. 2014

7. Nowbar AN et al, BMJ. 2014; 348: g2688.
Discrepancies in bone marrow stem cell trials
and enhancement of EF (DAMASCENE)

8. Meta-Analysis of Cell-based CaRdiac stUdiEs
(ACCRUE) in Patients with Acute Myocardial Infarction
Based on Individual Patient Data.
No effect of cell therapy on death (1.4% vs 2.1%) or death/re-
AMI/stroke (2.9% vs 4.7%) , change in ΔEF (mean difference:
0.96%, 95%CI: -0.2;2.1), ΔEDV, or ΔESV was observed compared to
controls.
Cell Therapy
Control
Gyongyosi, M et al, Circ Res Online

9. • How strong is the data supporting the
cardiac cell therapy ?
Promising Therapy or Great Potential?
• What are the effects of cell transplantation
in human hearts?

10. How do you assess effects of cell
therapies directly in human hearts
Patient needs LVAD as
bridge to cardiac
transplantation
Patient undergoes
cardiac transplantation
Open heart procedure
Heart accessible
Tissue removed for LVAD
Heart harvested,
Tissue available for examination

11. Do bone marrow-derived cells
induce cardiac regeneration?
CliniMACS Selection
CD34+
Stem Cells
CD34-depleted
no stem cells
BM Cells
Iron nano-
particle
labeling
BMMC

12. Patient identified as
needing LVAD LVAD placed Cardiac
transplantation
Bone marrow
processed into
fractions and
labeled
Heart explanted,
processed for
histologyBone marrow
aspiration
Bone marrow
fractions
injected into
heartPatient screened
and consented
75-240 days24 hours
Experimental Design
BMMC
Stempien-Otero et al, JACC in press

13. BM-derived Cells Do Not Improve
Vascularity or Fibrosis
202530354045
PicRed
Treatments
PicRed Saline CD34+ CD34neg BMMC
0.0000.0050.0100.015
CD31
Treatments
CD31
Saline CD34+ CD34neg BMMC
%CD31+area
%picrosiriusredarea
Endothelial Density Fibrosis
*
* P = 0.02 by paired t-test versus saline; dots represent mean values +/– SEM
Stempien-Otero et al, JACC in press
These studies could not address whether transplanted
cells induced endogenous repair mechanisms

14. • Engraftment is very poor (typically <1%).
• Durability of transplanted cells is questionable.
• Perhaps modest improvements in LV function.
• It is very unlikely that bone marrow-derived cells
directly result in myocyte regeneration.
• Only a large randomized clinical trial will resolve the
question of their efficacy
Conclusions after >10 years of clinical
studies of cardiac cell therapy with BMSC

15. Mastering the "hype" that typically follows
the introduction of new technologies
J. Fenn; Understanding Gartner's Hype Cycles, 2008. Harvard Business Press.