STEM CELL TRANSPLANTATION FOR HEART FAILURE

WHICH CELL BEST?

HEART FAILURE

Inability of the heart to pump

CauseIschemic

Nonischemic

Pathogenesis cell death/inflammation/scar/loss of contractility

Natural history5-year mortality of approximately 50% .

Financial BurdonHF creates a heavy burden on health care resources

Medical Rx improve symptoms and can prolong life

but are unable to replace scar tissue or awaken hibernating myocardium via angiogenesis.

HYPOTHESIS

Reduce scar

Increase number of effective myocardial cells

Increase number of blood vessels

Improve cardiac function

THUMBNAIL

Types of stem cells

Delivery techniques of various stem cell

Advances, challenges, and future directions of stem cell transfer for heart failure

ISCHEMIC HEART FAILURE

NONISCHEMIC HEART FAILURE

DO NOT REMAIN FOR A FEW DAYS!

Paracrine factors-well knownNeovascularization and remodelling

Endogenous cell recruitment ?

Homing and grow ?

Fusion to hybrid cell and multiply ?

Mirotsou M, Jayawardena TM, Schmeckpeper J,et al. Paracrine mechanisms of stem cell reparative and regenerative actions in the heart. J Mol Cell Cardiol 2011;50(2):280–9.

CELL TYPES

Skeletal Myoblasts

Peripheral Blood Cells

Bone Marrow Mononuclear Cells

Autologous Cultured Bone Marrow Cells

ne Marrow Mesenchymal Stem Cells

Adipose-Derived Stem Cells

Umbilical/Placental/Endometrial Mesenchymal Stem Cells

Cardiac Stem Cells

Embryonic and Induced Pluripotent Stem Cells

WHICH IS BEST ?

STEM CELLS

SKELETAL MYOBLASTS

1. Progenitor cells from skeletal muscle

2. First cells to be tested in both preclinical and clinical studies

3. Early clinical studies reported engraftment and significant improvement in cardiac function BUT subsequent clinical studies, including a 97-patient phase II randomized, placebo-controlled, double-blind trial, failed to reproduce these results

4. Ventricular tachyarrhythmia were noted after cell transplantation

5. A limited role in cell-based therapy for HF

PERIPHERAL BLOOD CELLS

1. CD34+ cells for ischemic HF with promising results

2. IssuesGranulocyte colony-stimulating factors for peripheral blood mobilization, apheresis, and the costs associated with CD34+ selection have limited the use of this cell product. The long-term benefits of using blood-selected cells in patients with acute myocardial infarction have been shown to be less favourable compared with using bone marrow cells. This finding has further limited the use of peripheral blood for treating ischemic heart disease. The mechanism of possible benefit for peripheral blood CD34+ cells in patients with nonischemic versus ischemic HF has not been identified.

BONE MARROW MONONUCLEAR CELLS

1. Heterogeneous

2. Early preclinical clinical studies Transdifferentiation into cardiomyocytes and supporting vasculature, resulting in improved left

ventricular function

Angiogenesis but no vasculogenesis

Faint improvent in EF with Autologous Stem Cells for

3. A recent trial (PreSERVE-AMI) : intracoronary bone marrow–selected CD34+ cell delivery in patients with post–myocardial infarction LV dysfunction, demonstrating that a minimum dose of 20 × 10 6 cells were required to show potential benefit

4. The purification of BMMNCs from bone marrow can be performed easily using density gradient centrifugation, and now can be performed at bedside using commercial cell processing systems

5. Processing bone marrow cell has non uniform standard world wide

6. BMMNCs in ischemic cardiomyopathy is safe and feasible

7. Significant positive clinical outcomes are limited

AUTOLOGOUS CULTURED BONE MARROW CELLS

As a result of the many issues related to rapid processing of autologous bone marrow, culture processes were developed to address issues with BMMNCs, specifically donor age and comorbidities

Lxmyelocel-T is a product derived from a small sample of autologous bone marrow that is cultured for 12 days. The culture process results in an enhanced product of mesenchymal cells and M2 macrophages, which have the potential for angiogenesis and remodelling of fibrosis

IMPACT-DCM trial :Benefit in only patients with ischemic HF

C-CURE (C-Cure Clinical Trial) program harvested a small amount of autologous bone marrow, which was cultured for several weeks in a cardiopoetic cocktail of growth factors CHART-2 (Congestive Heart Failure Cardiopoietic Regenerative Therapy), a global phase III study)

Benefits in patients with ischemic HF

BONE MARROW MESENCHYMAL STEM CELLS

Potential

Easily harvested and cultured

Immune-modulating and anti-inflammatory properties, making them immune-privileged. MSCs typically express CD105, CD73, and CD90, but lack hematopoietic markers (CD45, CD34, and CD14/CD11b)

Preclinical studies in ischemic and nonischemic cardiomyopathyAngiogenesis, reduced fibrosis, and improved cardiac function

Clinical study in ischemic cardiomyopathy: improved patient functional capacity, quality of life, and ventricular remodelling

Better than BMMNCs

Potential to be used as an allogeneic cell source, which leads to a very stable and reliable cell source

Endocardial delivery of allogeneic bone marrow MSCs[DREAM-HF trial] in pipe line

ADIPOSE-DERIVED STEM CELLS

Adipose-derived stem cells (ADSCs) also are a form of MSCs but are more abundant than bone marrow MSCs

PRECISE trial (A Randomized Clinical Trial of adiPose-deRived stEm& Regenerative Cells In the Treatment of Patients With Non revaScularizable ischEmic Myocardium) used autologous ADSCs in patients with HF demonstrating a modest potential benefit

ADSCs are more difficult to process and have been used strictly in an autologous manner, unlike bone marrow MSCs

Some preclinical models of allogeneic use of ADSCs have shown benefit in cardiac models, which also resulted in allogeneic immune responses

UMBILICAL/PLACENTAL/ENDOMETRIAL MESENCHYMAL STEM CELLS

Several mesenchymal cells have been isolated from pregnancy and gynecologic organs that have potential benefit in HF models. They are all derived and used in an allogeneic manner. Limited information is available, but many of these cells are being used in preclinical or early clinical trials

CARDIAC STEM CELLS

Preclinical models using various CSC populations have demonstrated their therapeutic potential

Intracoronary

SCIPIO- improvement in global and regional left ventricular function and a reduction in infarct size

CADUCEUS- benefit in scar reduction

Tseliou and colleagues-Cells can be made allogeneic from donor hearts

ALLSTAR-Allogeneic CSCs in patients with myocardial ischemia and decreased left ventricular function

DYNAMIC-in pipe line

EMBRYONIC AND INDUCED PLURIPOTENT STEM CELLS

Engraftment in prehuman models of HF

Sheets of cells have also been used in prehuman models showing functional engraftment, but translation to humans has also been difficult because of the scalability of manufacturing large sheets of cells

First-in-man study (ESCORT) in pipe line

ANTEGRADE VS RETROGRADE

1. Intramyocardial via an endocardial or epicardial approach

2. epicardial patch

3. Intracoronary

4. Intravenous

5. coronary sinus

INTRAMYOCARDIAL

Epicardial

1. Epicardial and endocardial approaches

2. Direct injection of cells into the heart muscle

3. Very accurate and reproducible but is invasive, because it is typically performed under direct vision either during a median sternotomy, video-assisted thoracoscopic surgery, or pericardioscopy

4. Best suited for combined procedures in patients who are undergoing surgery, such as the delivery of cell therapy during coronary artery bypass grafting, valve surgery, ventricular assist device implantation or transmyocardial laser revascularization

Endocardial

1. Less invasive and direct

2. Delivery of cells to target peri-infarct regions

3. Potential for cell loss during delivery.

4. Myocardial injury, inflammation, and scarring, all of which disrupt the conduction pathways and can contribute to arrhythmias

5. Perforation of a thinned or damaged ventricle. Endomyocardial delivery of cells also results in localized islets of cells rather than a homogeneous distribution, and access to regions of the heart other than the left ventricle remains difficult.

ENDOCARDIAL : MOST USED TECHNIQUE

Intramyocardial protocols1. Electromechanical mapping catheters (NOGA,

Biologics Delivery Systems, Irwindale, CA, USA), which allow real-time evaluation of myocardial viability before cell therapy injection

2. BioCardia Helical Infusion Catheter (HIC-BioCardiaInc, San Carlos, CA, USA)

3. C-Cath (Cardio3 Biosciences, Mont-Saint-Guibert, Belgium), which has a curved end needle to minimize the risk of perforation

INTRACORONARY

1. Infusing cells antegrade

2. Combined with open heart surgical procedure

3. Relies on cell migration through the endothelial layer of the artery, and homing of cells to damaged tissue

4. Occluded vessels prevent infused cells from reaching the myocardium

5. Janus phenomenon : This double-edged sword of angiogenesis versus accelerated atherogenesis has been termed the and has been seen in the setting of accelerated stenosis within coronary stents after intracoronary infusion of peripheral blood stem cells and bone marrow–derived stem cells

6. Artery occlusion or embolization

7.

INTRACORONARY FOR RESEARCH ONLY

1. Infusion time is limited because of antegrade block

2. Repeated instrumentation of, or balloon inflation within, the coronary arteries risks dislodging plaque or causing endothelial damage that serves as a nidus for plaque formation

3. The muscular wall of the arteries (compared with thinner-walled veins) presents a further distance through which delivered cells must migrate to reach the target myocardium

4. Generally been considered safe, several papers highlight unique risks of the procedure

5. Accelerated atherosclerosis or restenosis

6. TOPCARE-CHD –dissection

7. Less preferred to Endocardial cell delivery

INTRAVENOUS

1. Preclinical studies demonstrate low retention rates in the heart and significant cell trapping in the lungs

2. The intravenous route relies entirely on the homing of stem cells to the site of injury, and without means to augment or facilitate localization, sufficient cells are unlikely to be delivered to injured myocardium to demonstrate a clinical effect

3. Not currently used for clinical trials.

CORONARY SINUS

Less invasive and presents a lower risk than the left-sided arterial access required for antegrade intracoronary delivery

The retrograde route is well suited to “no-option” patients with significant coronary disease or thin myocardial walls, and allows for the safe and repeated delivery of cell therapy

longer infusion and dwell times may be used than with antegrade coronary delivery

Uniform distribution of cells, avoids the islet-like clustering and arrhythmias associated with intramyocardial delivery, and allows distribution to ischemic zones that cannot be accessed via the antegrade route because of diseased coronary arteries

Cell delivery also possible with CRT (LV lead in situ)

This method of delivery can be used in patients with ischemic and nonischemic

EPICARDIAL PATCHES

Prepare sheets of cell

Preclinical models

sternotomy or thoracotomy for implantation

TRIALS…..

Trial Cell Type End No Route Cause

MARVEL Skeletal muscle Safety + QOL 170 Endocardial Ischemic

FOCUS-HF BMMNC vs placebo LVESV 92 Endomyocardial Ischemic

Pokushalov et al BMMNC LVEF 109 Endomyocardial Ischemic

REGEN-IHD

Intracoronary

BMMNC + G-CSF vs

endomyocardial

BMMNC + G-CSF

vs G-CSF vs placebo

LVEF 148 Intracoronary/Endomyo

cardial Ischemic

DANCELL-CHF Repeated BMMNC LVEF 35 Intracoronary Ischemic

REVIVE-1 BMMNC vs medical

therapy Safety + SAE 60 Retrograde Ischemic

PreSERVE-AMI BMMNC vs placebo Safety + SAE 160 Intracoronary Ischemic

TRIALS…..

BAMI BMMNC vs placebo All-cause mortality 3000 Intracoronary Ischemic

REPEAT Single vs repeated (2

times) BMC infusions Mortality + morbidity 676 Intracoronary Ischemic

Patel et al BMMNC/CD34+ vs

placebo LVEF 50 Epicardial Ischemic

Patila et al BMMNC vs placebo LVEF 104 Epicardial Ischemic

PERFECTBone marrow CD133+

vs placebo LVEF 142 Epicardial Ischemic

PRECISE ADSC vs placebo SAE + infarct size 27 Endomyocardial Ischemic

Parcero et al ADSC Safety + QOL 10 Endomyocardial/Intrav

enous Ischemic

Yan et al Allogeneic USCs Safety + LVEF 10 Endomyocardial Ischemic

CHART-1 Cultured bone marrow

-cardiopoetic Time to SAE 240 Endocardial Ischemic

TAC-HFT

MSCs (100 or 200

million) vs BMCs (100

or 200 million) vs

placebo

SAE + LVEF 67 Endomyocardial Ischemic

TRIALS…..

Anastasiadis et al Allogeneic MSCs LVEF 30 Epicardial Ischemic

IxCELL DCM Cultured bone marrow Time to SAE 108 Endomyocardial Ischemic

PROMETHEUS Low- vs high-dose

MSCs vs placebo SAE 7 Endomyocardial Ischemic

MSC-HF MSCs vs placebo LVEF 60 Endomyocardial Ischemic

SCIPIO Cultured cardiac

progenitors SAE 33 Intracoronary Ischemic

Perin et al

25 vs 75 vs 150 million

allogeneic MSCs vs

placebo

Safety + LVEF 60 Endomyocardial Both

IMPACT-DCM Cultured bone marrow Safety + SAE 60 Endomyocardial/Epicar

dial Both

DREAM-HF Allogeneic MSCs Time to SAE 1730 Endomyocardial Both

POSEIDON-DCM MSCs vs allogeneic

MSCs Safety + SAE 36 Endocardial Nonischemic

TRIALS…..

Vrtovec et al G-CSF/blood/CD34+ LVEF 60 Intracoronary/Endomyo

cardial Nonischemic

DYNAMIC Allogeneic cardiac

progenitor cells Safety + SAE 42 Intracoronary Nonischemic

TOPCARE-DCM BMMNC LVEF 30 Intracoronary Nonischemic

Martino et al BMMNC LVEF 24 Intracoronary Nonischemic

Trial Cell Type End No Route Cause

MARVEL Skeletal muscle Safety + QOL 170 Endocardial Ischemic

FOCUS-HF BMMNC vs placebo LVESV 92 Endomyocardial Ischemic

Pokushalov et al BMMNC LVEF 109 Endomyocardial Ischemic

REGEN-IHD

Intracoronary

BMMNC + G-CSF vs

endomyocardial

BMMNC + G-CSF

vs G-CSF vs placebo

LVEF 148 Intracoronary/Endomyo

cardial Ischemic

TRIALS…..

DANCELL-CHF Repeated BMMNC LVEF 35 Intracoronary Ischemic

REVIVE-1 BMMNC vs medical

therapy Safety + SAE 60 Retrograde Ischemic

PreSERVE-AMI BMMNC vs placebo Safety + SAE 160 Intracoronary Ischemic

BAMI BMMNC vs placebo All-cause mortality 3000 Intracoronary Ischemic

REPEAT Single vs repeated (2

times) BMC infusions Mortality + morbidity 676 Intracoronary Ischemic

Patel et al BMMNC/CD34+ vs

placebo LVEF 50 Epicardial Ischemic

Patila et al BMMNC vs placebo LVEF 104 Epicardial Ischemic

PERFECTBone marrow CD133+ vs

placebo LVEF 142 Epicardial Ischemic

PRECISE ADSC vs placebo SAE + infarct size 27 Endomyocardial Ischemic

Parcero et al ADSC Safety + QOL 10 Endomyocardial/Intraveno

us Ischemic

Yan et al Allogeneic USCs Safety + LVEF 10 Endomyocardial Ischemic

CHART-1 Cultured bone marrow -

cardiopoetic Time to SAE 240 Endocardial Ischemic

TAC-HFT

MSCs (100 or 200 million)

vs BMCs (100 or 200

million) vs placebo

SAE + LVEF 67 Endomyocardial Ischemic

Anastasiadis et al Allogeneic MSCs LVEF 30 Epicardial Ischemic

IxCELL DCM Cultured bone marrow Time to SAE 108 Endomyocardial Ischemic

PROMETHEUS Low- vs high-dose MSCs

vs placebo SAE 7 Endomyocardial Ischemic

MSC-HF MSCs vs placebo LVEF 60 Endomyocardial Ischemic

TRIALS…..

SCIPIO Cultured cardiac

progenitors SAE 33 Intracoronary Ischemic

Perin et al

25 vs 75 vs 150 million

allogeneic MSCs vs

placebo

Safety + LVEF 60 Endomyocardial Both

IMPACT-DCM Cultured bone marrow Safety + SAE 60 Endomyocardial/Epicar

dial Both

DREAM-HF Allogeneic MSCs Time to SAE 1730 Endomyocardial Both

POSEIDON-DCM MSCs vs allogeneic

MSCs Safety + SAE 36 Endocardial Nonischemic

Suzrez et al BMMNC LVEF 28 Intracoronary Nonischemic

Ribeiro et al BMMNC LVEF 234 Intracoronary Nonischemic

Vrtovec et al G-CSF/blood/CD34+ LVEF 60 Intracoronary/Endomyo

cardial Nonischemic

DYNAMIC Allogeneic cardiac

progenitor cells Safety + SAE 42 Intracoronary Nonischemic

TOPCARE-DCM BMMNC LVEF 30 Intracoronary Nonischemic

Martino et al BMMNC LVEF 24 Intracoronary Nonischemic

THE STEM CELL CONUNDRUM

Well-designed, large-scale, randomized clinical trials with objective end points will help to fully realize the therapeutic potential of cell-based therapy for treating heart failure

DIFFICULT ROAD OFTEN CARRIES TO A BEAUTIFUL DESTINATION