Cardiac regeneration: mending the broken heart

1. Cardiac regeneration:mending the broken heart Marc Pfeffer MD PhD Professor of Medicine Harvard Medical School Boston, Massachusetts Piero Anversa MD Director, Cardiovascular Research Institute New York Medical College Valhalla, New York Victor Dzau MD Physician-in-Chief Brigham and Women’s Hospital Boston, Massachusetts

2. Quantum leaps forward • Major advances come in quantum leaps, and then we fine-tune them. We think we are at the crux of a new breakthrough. • what are the new discoveries based on? • how sound is this foundation? • where are we going from here?

3. Regenerative hearts • Until recently, we were told the heart is terminally differentiated: • “What you have is what you will die with.” • Pfeffer

4. Primitive cells • Considering the heart an organ that cannot repair itself is wrong. • Anversa • The question is: do we have a primitive, undifferentiated cardiac cell that can generate all the cells in the heart? • If they do exist, where do they originate?

5. Isolated regeneration • Why do the myocytes not move into the infarcted area and repair it? • So far, the regeneration has been seen only in the surviving myocardium in the area next to the infarct

6. Death vs regeneration • We think so many patients develop heart failure after infarct because the balance between the cell-death processes (both apoptosis and necrosis) and regeneration favors cell death in end-stage failure We don't know the timing: how long does it take a cell to die by necrosis, to die by apoptosis, or to regenerate? Anversa

7. Enhancing regeneration • "If we can agree that there is balance here between death and regeneration, if that concept can be developed further, then what's so exciting about this is that in the future we will […] have the new tool of enhancing regeneration." • Pfeffer

8. Regenerative capacity • Regenerative capacity is like a bank account • After an MI, do you have sufficient capacity to repair a myocardium that is injured? • If it is a small infarct, we can sometimes repair it completely • If the infarct is too large, the mechanism is insufficient

9. Pathological enlargement • "In heart failure, I think the horse is out of the barn." • Dzau • Because you've already gotten to the stage where there is pathological enlargement, the repair mechanism cannot turn the condition around

10. Stem cell source

11. Harvesting cells • Can harvest the primitive cells by removing the blood elements (white blood cells, red blood cells, and platelets) • Cells can be injected directly into the injured heart • Or they can be mobilized out of the marrow with cytokines

12. Questions • Does this prevent further cardiac dilatation after injury? • Is it mainly the formation of new blood vessels that's important? Or does it just provide more myocytes to work with? • What is the timing needed? • How do we best tap the therapeutic potential?

13. Is the cell source important? • Do we care where the cells come from? • Yes. A primitive cell in the heart is already programmed to produce everything in the heart • A primitive heart cell should be naturally more effective • Anversa

14. Two viewpoints • Biological viewpoint: primitive heart cells from the myocardium will be programmed to work the right way without modification • Practical viewpoint: bone marrow cells are easy to find, and the ischemic environment seems to push them along the right path to form myocytes • Dzau

15. The here and now • Autologous skeletal myoblasts are being injected into infarcted myocardium • How do we put outside contractile tissue into a hostile environment and get it to work? • We need the whole myocardium

16. Limits of skeletal myoblasts • Skeletal myoblasts aren't able to generate new tissue • There is no real electrical coupling between the cells with skeletal myoblasts, even though they contract • "I think there are some problems with the skeletal myoblasts that I don't know whether they will be resolved soon." • Anversa

17. Proof of concept • Let's look at skeletal myoblast as proof of concept • If we put a skeletal myoblast into the heart, we generate muscle • If we have some muscle in an area that is dilating, it seems to help prevent further dilation

18. More myoblast questions • Myoblast cells don't form syncytium and so cannot coordinate electrical and mechanical activity • Reports of people doing better may reflect the heart not dilating as much, not an improvement in contractility

19. Islands of arrhythmogenicity • These areas could develop into islands of arrhythmogenicity, foci for ventricular arrhythmia • 4 out of 12 of the patients from France are receiving ICDs • It is much better to go with a primitive cell to create myocytes, or to create more blood vessels with angioblasts

20. What next? • We are already harvesting marrow cells by simple aspirate and trying to form cardiomyocytes • fortunately this is not technically hard to do • unfortunately we need a lot more careful experimental data Dzau

21. Patient safety • We want to do good, and do no harm, so we need to know more: • when is the best time to do this? • what is the right environment? • what's the best way to isolate these cells?

22. The future • Injecting cells into systemic circulation • Using the right cocktail cytokine to free cells from bone marrow • Activating the theoretical primitive stem cell already in the myocardium

23. Controlled experiments • It is too early to go to humans yet • "If we can identify the mechanism of this turnover and enhance this turnover, we may be able to use the same process for repairing the heart.“ • Anversa

24. Stem cell controversy • We are talking here about using autologous or primitive cells within the adult tissue, not embryonic cells • These eliminate the need for immunosuppression or other transplant problems • However the overall potential of adult cells is lower than embryonic cells • Dzau

25. Remodeling process • “The remodeling process is the enemy. The infarct is the beginning of an opportunity to alter the remodeling process.” • Pfeffer

26. Physician’s tools • For the practicing physician we have: • preventive medicine • infarct limitation therapies • for certain patients there will be a balance between hypertrophy, their intrinsic capacity to restore function, and reperfusion

27. Mending the broken heart • 90 days after anterior MI, 1/3 of the patients have no regional wall-motion abnormality or enlargement on echo • We must learn to tweak this balance of natural regeneration from 1/3 of patients to 2/3 or even more in the future • Pfeffer