cell therapies in heart failure thet don't work
TRANSCRIPT
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
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
Eje
ction f
raction (
%)
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
• 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?
Sadat, K et al, J Nucl Cardiol. 2013
Impact of bone marrow cell therapy on left
ventricular ejection fraction after MI (2013)
Cardiac cell therapy improves mortality in
patients with heart failure
Fisher SA et al, CircRes Online
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
Nowbar AN et al, BMJ. 2014; 348: g2688.
Discrepancies in bone marrow stem cell trials
and enhancement of EF (DAMASCENE)
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
• 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?
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
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
Patient identified as
needing LVAD LVAD placed Cardiac
transplantation
Bone marrow
processed into
fractions and
labeled
Heart explanted,
processed for
histology Bone marrow
aspiration
Bone marrow
fractions
injected into
heart Patient screened
and consented
75-240 days 24 hours
Experimental Design
BMMC
Stempien-Otero et al, JACC in press
BM-derived Cells Do Not Improve Vascularity or Fibrosis
20
25
30
35
40
45
PicRed
Treatments
Pic
Re
dSaline CD34+ CD34neg BMMC
0.0
00
0.0
05
0.0
10
0.0
15
CD31
Treatments
CD
31
Saline CD34+ CD34neg BMMC
% C
D31+
are
a
% p
icro
sir
ius r
ed a
rea
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
• 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
Mastering the "hype" that typically follows
the introduction of new technologies
J. Fenn; Understanding Gartner's Hype Cycles, 2008. Harvard Business Press.