1. Translational Research for Myocardial Regeneration 2016
Timothy D. Henry, MD
Director of Cardiology
Cedars-Sinai Heart Institute

2. DISCLOSURE
Baxter, Cytori, Aastrom, Capricor, Cardio3, NHLBI all for Cell Therapy trials

3. Cardiovascular Disease Targets
Refractory angina
Acute myocardial infarction
Congestive heart failure
Ongoing ischemia
Previous MI
Nonischemic
Peripheral arterial disease
CLI
Claudication

4. Ischemic Heart Failure Progression vs Therapeutic Options
Novel approaches to fill
the gap
Therapy
Medical
Health status
+ CRT
Several novel approaches are being tested to fill this therapeutic gap. On one hand, there are novel devises tested for the specific subsets of heart failure patients.
On the other hand, a broad range of biologics including cellular interventions is being introduced.
So this is the positioning of the cell therapy in the current heart failure management.
LVAD → HTx
NYHA I NYHA II NYHA III NYHA IV
Bartunek J and Vanderheyden M (Eds): Translational Approaches to Heart Failure, Springer 2013

5. Are All CHF Pts Created Equal?
45 yo s/p Ant MI 6 yrs ago with LVEF 35%, Class 3 sxs, Patent LAD stent
50 yo s/p CABG in1998 with occluded grafts but patent LIMA, LVEF 35%, Class 3 sxs
48 yo nonischemic cardiomyopathy of uncertain etiology, LVEF 35%, Class 3 sxs

6. Cell Therapy: Changing Paradigm?

7. Am J Cardiol 2013;112:

8. Kandala Meta-analysis
LVEF
LVESV
LVEDV
Am J Cardiol 2013;112:

9. LVEF IM IC
Am J Cardiol 2013;112:

10. PLoS One 2013 Jun 19;8(6):e64669

11. Mortality
PLoS One 2013 Jun 19;8(6):e64669

12. Martin-Rendon Meta-analysis
Angina Class
Angina Frequency
PLoS One 2013 Jun 19;8(6):e64669

13. Martin-Rendon Meta-analysis
Quality of Life
Exercise Time
LVEF
PLoS One 2013 Jun 19;8(6):e64669

14. Study Flow Screening 550 pts 2:1 Randomization 30 pts Treatment Group
30x106 BMMNC
20 pts
LVA/ NOGA
Cell Injection/
Mock Injection
Control Group
Mock BM Harvest
10 pts
Early Assessments
3 Month Assessment
- CCS SPECT
- NHYA Echo
- Holter MVO2
MRI Subgroup
17 pts
6 Month Assessment
- CCS SPECT
- NHYA Echo
Holter MVO2
NOGA Cor/LVA
Crossover
8 pts

15. Cell Analysis Immunophenotyping: Hematopoietic: Endothelial:
CFU-GM
Immunophenotyping:
Surface markers (CD 34+, 133+,)
Hematopoietic:
CFU-GM
Endothelial:
Tube Formation
Ac LDL incorporation
Mesenchymal:
CFU-F
Population doubling time
Chemotaxic properties:
migration (SDF-1, VEGF)
Hindlimb ischemia:
immunodeficient murine model
Tube Formation
New slide
CFU-F

16. Mesenchymal Colony Forming Units
(CFU-F)
Patient ID
180
CFU Number per 106 BM Mononuclear Cells

17. MSC Growth Kinetics
Control
Cell Number (103)
Time (hours)

18. FOCUS-2 Rationale-Endpoints
Severe ischemic LV dysfunction (<45%) n= 86 pts
Increased dose (100M cells)
Multicenter-CCTRN
Placebo controlled
Combined Endpoints = SPECT, Echo (LVV), MVO2 (all core assessed)
Late Breaking Trials ACC 2012-JAMA

19. LVEF
Baseline-6mo: Sig increase in LVEF change BMC vs Placebo (+1.4 vs -1.3, p=0.03)
BMC
Baseline
N=54
6 Mo
N=28

20. Correlation ΔLVEF and %CD34
Unadjusted
Adjusted for Age and Therapy
ΔLVEF
ΔLVEF
%CD34
R2= 8%
P = 0.012
R2= 16%
P=0.043

21. Relationship of Age (prespecified)
Delta LVEF and Age
Placebo
BMC
BMC
R2= 10%
P = 0.017
Placebo
R2= 2%
P= NS

22. Strategies to Enhance Cell Therapy
Increase the number of cells (autologous)
Whole bone marrow (Harvest)
Selected cells (autologous)
Adipose derived cells (Cytori)
CD34+ cells (Baxter)
ALD-bright (Aldagen)
Corrected spelling of Caduseus.

23. ADRC Therapy Adipose tissue is processed at the point of care
>100 cc Fat
(adipose) tissue
from minor liposuction
Celution® System:
point-of-care device
CE Mark since 2007
Adipose-derived stem &
regenerative cells (ADRCs)

24. Adipose-Derived Regenerative Cells
ADRCs:
A fresh (non-cultured) clinical grade & clinically relevant heterogeneous
population of cells from the Stromal Vascular Fraction (SVF) of cells from adipose 24

25. ATHENA Study Design
Prospective, Randomized, placebo-controlled, double-blind safety and feasibility study
45 patients LVEF < 45% with evidence of ischemia
Same-day liposuction and intramyocardial injections of autologous ADRC prepared using the investigational Celution® System or placebo
2:1 ADRC:placebo
ADRC dose: 0.4x106 cells/kg or a max 40x106
Follow up visits through to 5 years post-injection

26. Strategies to Enhance Cell Therapy
Increase the number of cells (autologous)
Whole bone marrow (Harvest)
Selected cells (autologous)
Adipose derived cells (Cytori)
CD34+ cells (Baxter)
ALD-bright (Aldagen)
Expand and/or enhanced cells (autologous)
Aastrom Biosciences
C-Cure
MSC-HF
Corrected spelling of Caduseus.

27. Ixmyelocel-T: Key effector cells are M2-like Macrophages and MSCs
It is well-accepted that there are multiple cell populations and multiple redundant signaling pathways involved in the cascade that leads from tissue injury to chronic inflammation and ultimately to tissue damage and loss of organ function or tissue repair. Therapeutic approaches targeting single signaling pathways in these complex disease and repair processes have not proven effective, and most cell therapy approaches utilize a single cell type to attempt to arrest these disease processes and repair tissue. Aastrom is taking the therapeutic approach of developing multicellular therapies that use the cell populations that the body naturally uses to repair and regenerate damaged tissue.
IXMT is a highly differentiated product in that it is the only multicellular therapy that contains expanded populations of both mesenchymal stromal cells, or MSCs, and alternatively activated M2-like macrophages, two cells populations that are known to play a key role, individually and collectively, in promoting tissue repair and regeneration. Starting with a small volume of a patient’s bone marrow, certain cell populations such as RBCs, lymphocytes and granulocytes are reduced, while these key tissue repair cell populations are expanded through Aastrom’s proprietary manufacturing process.

28. Ixmyelocel-T: Phase 2a MACE events in Ischemic DCM Groups
41% reduction in the number of patients having a MACE event at 12 months

29. Ixmyelocel-T: Phase 2a Ischemic DCM groups: NYHA Class* * * *
And in looking at secondary efficacy measures in the ischemic DCM groups, consistent positive trends were observed in the IXMT treated groups in symptomatic efficacy measures, as demonstrated by post baseline improvement in NYHA class.
All patients were NYHA III or IV at baseline.
*Combined IMPACT-DCM and CATHETER-DCM data in the ischemic DCM groups. * p <0.05

30. The ixCELL-DCM Trial: Study Design
Double-blind, randomized trial.
Following the screening period, patients will be randomized in a 1:1 ratio to ixmyelocel-T or vehicle control. The same day as randomizations, patients will undergo the bone marrow aspiration (approx. on Day -15).
On Study Day 1 all patients will undergo cardiac catheterization with NOGA mapping and injections. Injections will be directed into viable myocardium near infarcted tissue (border zone of infarct). If no infarct, inject into viable, ischemic myocardium (if able to determine areas of ischemia). Following injection procedure, patients will remain over night for monitoring.
Post-injection study visits will occur at Months 1, 3, 6, 12. Primary data analysis will occur after all patients complete Month 12 visit. Patients will be followed between Month 12 and 24 to collect SAEs only (no clinic visits are scheduled during this time.).
Investigational product volume ~ ml: administered via NOGA map determined transendocardial injections; ~200 million cells
Confidential

31. C-CURE FIM Trial
The C-Cure trial demonstrates the feasibility and safety of cardiopoietic mesenchymal stem cells in patients with ischemic cardiomyopathy
Complementing standard of care, C-Cure therapy improved cardiac function and clinical performance
The favourable profile supports follow-up pivotal studies in a larger patient population
And we have heard earlier this morning the trial
In its totality, the C-Cure trial was important in establishing the first clinical experience and future leads for the ensuing trial at three levels: manufacturing, delivery and design and methodology;

32. Second Generation of Cell Therapy
to Ensure Cardiac Lineage Specification
Discovery
Translation
Application
Cell Therapy GF
Naïve MSC
Decoding natural
cardiopoiesis
Pre-clinical
assessment
GMP Scale-up
C-CURE trial
CP MSC
Lineage
specification
At the level of the cell product optimizaiton, let me reiterate that Andre Terzic and Atta Behfar.
By decoding natural cardiopoiesis derived a cardiogenic cocktail capable to prime consistently patient-derived mesenchymal stem cells into cardiac progeny.
In preclinical studies, these primed cardiopoietic stem cells demonstrated superior benefit as compared to their unprimed, naïve source.
This in tandem with GMP scale up and quality control was the basis for the C-Cure trial.
Nature Clin. Pract. 2006, 2007; J Ex Med 2007; Gen. Biol. 2008; Stem Cells, 2008, 2009; JMCC 2008; JACC 2010; Cell Transplant 2011

33. C-CURE International Program
Congestive Heart Failure
CArdiopoietic Regenerative Therapy (CHART-1) Trial
Efficacy and safety of bone marrow- derived mesenchymal cardiopoietic cells (CRBS-CQR-1) for treatment of chronic advanced ischemic heart failure
Prospective, multi-center, randomized, sham-controlled, double-blinded study
240 subjects: 2 arms
Standard of Care + cardiopoietic cells
Standard of Care + sham procedure
Based on this advances the Chart 1 trials
ClinicalTrials.gov Identifier NCT

34. N=55, cultured autologous MSC
MSC-HF Trial
N=55, cultured autologous MSC

37. Strategies to Enhance Cell Therapy
Increase the number of cells (autologous)
Whole bone marrow (Harvest)
Selected cells (autologous)
Adipose derived cells (Cytori)
CD34+ cells (Baxter)
ALD-bright (Aldagen)
Expand and/or enhanced cells (autologous)
Aastrom Biosciences
C-Cure
MSC-HF
Allogeneic
MPC (Mesoblast-Teva)
MSC (Osiris)
MAPC (Athersys)
Corrected spelling of Caduseus.

38. Mesenchymal Precursor Cells (MPCs)
Heart muscle
MPC highly expandable
Cardiovascular disease therapies
Bone marrow + STRO-3+ antibody
Blood vessels
Magnetic beads
Pancreas
Diabetes, immunologic/
inflammatory conditions
Immune system
Bone
Culture- expanded cells
Orthopedic diseases
Isolated cells
MPC’s are immunoselected (based on Stro 3 antibodies) Allogenic cells derived from the bone marrow of a young healthy donor. The are culture expanded in a GMP facility.
Cartilage
Derived from young, healthy, unrelated donors
Well-controlled, large-scale cell expansion
FDA, EU, GMP, and ISO compliant manufacturing
Centralized manufacturing 38

39. Study Design
DESIGN: Single-blinded, dose-escalation, randomized, multicenter clinical trial
PRIMARY ENDPOINTS:
To evaluate the feasibility
and safety of transendocardial injection of MPCs
SECONDARY ENDPOINTS:
NYHA class
MLWHF
SF36
6 minute walk test
EF: Echo, MUGA
Spect Perfusion
MACE, Mortality
60 Patients
Cohort C
High Dose
150 M
15 Treated
5 Placebo
Cohort A
Low Dose
25 M
Cohort B
Med Dose
75 M
Time Points
Safety:
1, 2, 30, 90, 180, & 360 days
Efficacy:
3,6, & 12 months

40. Immunologic Monitoring Results
6 of 45 (13%) MPC-treated patients developed DSA.
Anti-HLA antibodies produced transiently (< 1 month):
4 of 45 (9%) total MPC-treated
Anti-HLA antibodies persisting > 1 month:
2 of 45 (4%) total MPC-treated
2 of 15 (13%) high-dose MPC (150M)
0 of 30 (0%) low and mid-dose MPC (25M and 75M)
All anti-HLA antibodies were against donor HLA class I.
No clinical symptoms/signs
No effect on outcome
Donor-Specific Anti-HLA Antibody Response
These are the results of immunologic monitoring.
Read.
Importantly there were no clinical signs or sx’s associated with the detection of DSA and no effect on outcome. 40

41. Changes in LV Ejection Fraction%
P=0.008
P=0.638
P=0.925
3 months
n=15
n=14
P=0.232
P=0.472
P=0.273
6 months
n=13
P=0.308
P=0.672
P=0.469
12 months
P=0.184
P=0.188
P=0.704 %
n=15
n=43
n=13
n=44
n=14
n=42
Here are the changes in LV ejection fraction.
Numerically the ef 41

42. Cardiac Death Free Survival
MACE Free Survival
Time to MACE (months)
All Subjects
Log-rank P value=0.036
Time to Cardiac Death (months)
Log-rank P value = 0.020
All Subjects
Time to MACE (months)
Ischemic Subjects
Log-rank P value = 0.024
Define MACE: Cardiac Death, revascularization, MI
MACE: Cardiac Death, Revascularization, MI 42

43. Strategies to Enhance Cell Therapy
Increase the number of cells (autologous)
Whole bone marrow (Harvest)
Selected cells (autologous)
Adipose derived cells (Cytori)
CD34+ cells (Baxter)
ALD-bright (Aldagen)
Expand and/or enhanced cells (autologous)
Aastrom Biosciences
C-Cure
MSC-HF
Allogeneic
MPC (Mesoblast-Teva)
MSC (Osiris)
MAPC (Athersys)
Cardiac derived
Caduceus (Capricor)
SCIPIO
Corrected spelling of Caduseus.

44. CADUCEUS Design
Post-MI (<30 days at screening) & LV dysfunction (EF 25-45%)
Randomized (2:1), controlled, dose-escalation safety and preliminary efficacy study (MRI for scar mass, viable mass, volumes, & function)
Two centers (Cedars-Sinai Heart Institute; Johns Hopkins)
Endomyocardial biopsies; CDCs manufactured at Cedars-Sinai Heart Institute
Intracoronary infusions of autologous CDCs

45. CDC therapy reduces scar and increases healthy heart muscle in CADUCEUS
Δ scar mass
Δ viable mass
6 mos
12 mos
p=0.001
p:0.01
p=0.001
p:0.02
n=8
n=15
n=7
n=8
n=8
n=15
n=7
n=8
All bars represent +/- 1 SEM

46. ALLogeneic heart STem cells to Achieve myocardial Regeneration
PIs: Tim Henry, Raj Makkar
Phase I/II study Post-MI EF: < 45%, IS > 15% (MRI)
Intracoronary infusion of allogeneic CDCs
Open-label Ph I (3 sites) followed by double-blind randomized placebo-controlled Ph II (20 sites)
Stratified patient recruitment (274 pts total)
30-90 days post MI (healing)
> 90 days post MI (chronic)
Primary efficacy enpoint: scar size
funded by NIH and CIRM grants to Capricor

47. Still not available at the florist yet….

48. We still need better Options!!
Will it be Cell Therapy??

50. Regenerative efficacy in CADUCEUS:
Representative MR images
baseline 6m
0005-CDC01-014
CDC-treated
0005-CDC01-002
Control

51. SCIPIO Post-MI LV dysfunction undergoing CABG (EF<40%)
Autologous cardiac stem cells (c-kit+) obtained at CABG from right atrium.
Open label, “block randomization due to most patients wanting CSCs”?
Cells expanded in Boston and delivered in Ky.
IC infusion (133 days): up to 1M cells
Bolli, Lancet 2011

52. SCIPIO
Bolli, Lancet 2011

53. MVO2 Patients >60 Years
p=ns
25.00
Treatment
Control
20.00
(ml/Kg/min)
15.00
10.00
5.00
Baseline
3 months
6 months

54. MVO2 Patients <60 Years
25.00
Treatment
Control
20.00
p=0.07
(ml/Kg/min)
15.00
p=ns
10.00
5.00
Baseline
3 months
6 months

55. 277 Active Network Members
Organizational Structure: NHLBI Cardiovascular Cell Therapy Research Network (CCTRN)
NHLBI
Skarlatos
PRC
DSMB
Chair
Simari
PDC
P & P
Steering Committee
Data Coordinating Center
UTSPH
Moyé
Cell
Processing
QC Lab
Biorepository, cMRI, Echo, MVO2, SPECT Core Labs
Skills
Development
Core
Skills
Development
Core
277 Active Network Members
Texas Heart
Institute
Willerson
U FL
Pepine
Cleveland
Clinic
Ellis
Minneapolis
Heart Institute
Henry
Vanderbilt
University
Zhao
Cell Processing
Cell Processing
Cell Processing
Cell Processing
Cell Processing
Satellites:
DeBakey VA
Satellites:
Pepin Heart Institute
Satellites:
University Hospitals
Satellites:
United Heart & Vascular Clinic
Metro Cardiology Consultants
U MN
Mayo Clinic 58

56. Primary Endpoint: LVESV
Baseline-6 mo: No difference in change BMC vs Placebo
Change in Indexed LVES Volume by Echo
BMC
Placebo
Need p value
Baseline
N=54
6 Mo
N=28

57. Primary Endpoint: MVO2
Baseline-6 mo: No difference in change BMC vs Placebo
BMC
Placebo
Baseline
N=54
6 Mo
N=28

58. Ischemic Heart Failure Progression vs Therapeutic Options
Unmet clinical need
Therapy
Medical
LVAD → HTx
Health status
+ CRT
Now question is what we can do for him, what options we have to halt the detrimental spiral of heart failure.
Well unlike in mild to moderate heart failure, we do not have many therapeutic options left with the current standard of care. His medical therapy has been optimized, he is not a CRT candidate and still does not qualify for the hemodynamic support or cardiac transplantation and patients with advanced heart failure like him represent the current unmet clinical need with the gap in the therapeutic options.
NYHA I NYHA II NYHA III NYHA IV
Bartunek J and Vanderheyden M (Eds): Translational Approaches to Heart Failure, Springer 2013

59. Strategies to Enhance Cell Therapy
Increase the number of cells (autologous)
Whole bone marrow (Harvest)
Selected cells (autologous)
Adipose derived cells (Cytori)
CD34+ cells (Baxter)
ALD-bright (Aldagen)
Expand and/or enhanced cells (autologous)
Aastrom Biosciences
C-Cure
Allogeneic
MPC (Mesoblast-Teva)
MSC (Osiris)
MAPC (Athersys)
Cardiac derived
Caduceus (Capricor)
SCIPIO
Corrected spelling of Caduseus.

60. ADRCs: Mechanism of Action
Wound remodeling
Differentiation
Angiogenesis
Paracrine
signaling
Prevention of
cell death
Modulation of Inflammation
Home to Injury

61. ADRCs Mechanism of Action in Wound Healing
Cell Sub Type
Mediator
Mechanism
Clinical Effect & Patient Benefit
 VEGF, PlGF, bFGF
 Vessel density
ADSCs
EPCs Mø
Endo
VSMCs
Pericytes
 Endothelial dysfunction
 NOS,  ROS
 Perfusion
Pericyte differentiation
& recruitment, SDF-1, PlGF
Vessel stabilization & expansion
 WBC recruitment & activation
ADRC
Mixed Cell
Population
ADSCs Mø
T cells
 IL-10,  IL-6
Disease
Stabilization
Symptom/Function
Benefit
 Inflammation
 PGE2
Mø switch to M2
 MMP1, TGFb,  TIMP1
 Scar remodeling Mø
EPCs Endo
ADSCs
 Recruitment of cardiac stem cells
 SDF-1, IGF-1
 Fibrosis
 HGF, IGF-1
 Myocardial apoptosis

62. Ixmyelocel-T: Phase 2a Clinical Trials
From a clinical perspective, Aastrom has completed two 12-month randomized open-label phase 2a studies in DCM patients that have guided the design of the current phase 2b program. The objectives of those studies were to demonstrate the safety and tolerability of IXMT in DCM patients, evaluate surgical vs. catheter-based delivery approaches, and define the optimal patient population for future clinical studies. To this end, Aastrom conducted both a surgical study (the IMPACT-DCM study) and a CATHETER-DCM study, both of which included ischemic and non-ischemic patient populations. The IMPACT-DCM data has been presented by Dr Tim Henry at the 2012 Society for Cardiovascular Angiography and Interventions (SCAI) meeting.
Henry et al., Circ Res 2014

63. Ixmyelocel-T: Phase 2a Ischemic DCM groups: 6MWD*
And in looking at secondary efficacy measures in the ischemic DCM groups, consistent positive trends were observed in the IXMT treated groups in the 6MWD. Baseline values for 6MWD were 386 m for control and 356 m for ix-T.
*Combined IMPACT-DCM and CATHETER-DCM data in the ischemic DCM groups. * p <0.05

64. Ixmyelocel-T: Phase 2a Ischemic DCM groups: MLHFQ
In the ischemic DCM groups, consistent positive trends were observed in the IXMT treated groups in functional measures such as Minnesota Living with Heart Failure Questionnaire (MLHFQ). Baseline values for MLHFQ were 54.9 for control and 48.4 for ix-T. Lower score indicates better emotional and physical function.
*Combined IMPACT-DCM and CATHETER-DCM data in the ischemic DCM groups.

65. Ixmyelocel-T: Phase 2a Ischemic DCM groups: LVEF%
And in looking at secondary efficacy measures in the ischemic DCM groups, consistent positive trends were observed in the IXMT treated groups in functional measures, such as improvement in ejection fraction as shown here. Graph shows the percent of patients who exhibited >5% increase in LVEF relative to baseline.

66. The ixCELL-DCM Phase 2b Trial
Phase 2b ixCELL-DCM Study Design
Objectives
To evaluate the efficacy, safety and tolerability of ixmyelocel-T compared to placebo in patients with heart failure (HF) due to ischemic DCM
Patients
Males and females, age 30-86
Diagnosis of ischemic DCM according to WHO criteria
Not a candidate for reasonable revascularization procedures
LVEF ≤ 35%
NYHA class III or IV heart failure
Recent HF-related hospitalization or recent outpt visit to treat decompensated HF
Design
Multicenter, randomized (1:1), double-blind, placebo-controlled phase 2b study
108 patients at approximately 35 sites in the US and Canada
Administration via catheter injection into the left ventricular endocardium using the NOGA® MyostarTM injection catheter
Key endpoints
Primary: Avg. number of clinical events (all-cause deaths, CV hospitalizations, and unplanned visits to treat acute decomp. heart failure over 12 months post injection (pbo vs ixmyelocel-T)
Secondary: Additional clinical, functional, structural, symptomatic/QOL, and biomarker measures at 3, 6 and 12 months
Status
First patient injected in April 2013; enrollment to complete in 2014
Phase 2b ixCELL-DCM Trial
Results from the two phase 2a trials demonstrated proof-of-concept for moving into a phase 2b study and formed the foundation for the design of the current Phase 2b ixCELL-DCM study. This study is a multicenter, randomized, double-blind, placebo-controlled study evaluating the efficacy and safety of IXMT in patients with advanced heart failure due to ischemic DCM. The study is designed to enroll 108 patients at approximately 35 clinical sites in the U.S. and Canada, and IXMT will be administered using the NOGA Myostar injection catheter system. The patient population is the same as in the phase 2a studies; namely advanced NYHA class III or IV heart failure patients with a diagnosis of ischemic DCM according to WHO criteria that are not candidates for reasonable revascularization procedures. The primary endpoint is the number of all-cause deaths and hospitalizations, and unplanned emergency room visits for IV treatment of acute worsening heart failure over 12 months. We will also be evaluating several secondary clinical, functional, and symptomatic efficacy measures at 3, 6, and 12 months.

67. CHART-1 Clinical Trial Major Inclusion Criteria
NYHA Class III or IV or INTERMACS class 4, 5, 6 or 7
Systolic dysfunction with LVEF <35%
Ischemic cardiomyopathy
6 min walk distance >100 m and <400 m
MN Living with HF score >30
Hospitalization for heart failure within past 12 months
AHA/ACC guidelines compliant heart failure management – stable therapy >3 months prior to screening visit

70. Ten years of Cardiac Regeneration
Stem cells target highly disrupted myocardial tissue with extensive remodeling, collagen accumulation and profound ultrastructural changes: Too complex to be reversed by stem cells?
There are at least 3 reasons for this pesimism
One is that naïve stem cells target highly disrupted myocardial tissue
We face extensive remodelling with collagen accumulation together with profound ultrastructural changes that maybe simply too complex to be reversed by stem cells to achieve clinically meaningful benefit
Courtesy Dr. M Novotova, Slovak Academy of Sciencies