Saturday, March 25, 2006

Stem Cell Therapy: The promises and the day after

Stem cell therapy was described here. We find it flattering that anyone would mention what we haven't covered. Hey, if someone notices what we haven't covered then they have to actually know what we covered. That's good to know. Bear in mind that the blog technician and the doctor live 5 time zones apart. Try to be understanding of the time lags we live with. Now on to the post....


We must begin by giving you all an introduction to stem cells. The beginning of life is the sperm fertilising the ovum, producing the zygote. This zygote has the potential to form all the cells, tissues and organs of the body. These embryonic stem cells are the most pluripotential or multipotential cells that we have. It can become any cell line that it is targetted for. Alas, research with them is restricted because of the potential to make (clone) humans (an ethical issue).

In the mother's womb, the cells divide, in a targetted manner to form tissue and tissue come together in a targetted manner to form organs, and organs come together in a targetted manner to form the complete human being, which make us the living miracle we are. However, as life progresses, tissue wears and tears, or gets injured. So we need to repair and regenerate, new cell for old. For these purposes, some cells in the body are reserved for repair and regeneration. As God has made us, some organs cannot regenerate. The cells that are injured and gone are injured and gone, eg the brain and nervous tissue.

For a long time, the heart was also thought not to be able to regenerate from injury. This is now thought not to be. Heart muscle cells can be regenerated. For tissue that repairs and regenerates, the regenerative cells can come from pluripotential cells in the tissue eg skeletal muscles, or from the bone marrow (the blood cell factory where cells are produced and then targetted to different cell lines). The cells with the potential to repair and regenerate, be it from skeletal muscles or from the bone marrow, have limited potential, this potential is obviously not as great as embryonic stem cells.

The failing heart

The most common cause of loss of cardiac muscle tissue with heart failure is coronary artery disease. Myocardial infarctions (heart attacks) kill cells. The longer the period of no blood flow (from coronary thrombosis) the greater the heart muscle cell destruction, and the poorer the resultant heart function. Opening heart arteries soon after the heart attack restores blood flow and potentially limits the amont of heart muscle damage. The sooner the heart artery is opened, the more the muscle can recover, and the lessed the damaged area.

Heart muscle damage shows itself in falling heart function, which may lead to heart failure, a syndrome of breathlessness and leg swelling. This heart failure can be treated with medical therapy, with good effect, especially if the heart failure is mild to moderate (reflecting a mild to moderate area of heart muscle damage). In severe heart failure (large, extensive heart muscle damage) medical therapy may not be adequate, and the patient may benefit from certain devices and ultimately may require cardiac transplantation.

Cardiac transplantation is a good and effective way to treat patients with severe heart failure from extensive heart muscle failure, not responsive to medical and device therapy. BUT, heart transplantation suffers from a severe lack of donor hearts. This has provided the impetus to find new ways to grow heart muscle cells, leading us to the area of stem cell therapy for the failing heart. This is an area of very active cardiac research. It holds great promise, but the promise has not yet been realised, as there are considerable problems to overcome.

Stem cell therapy for the failing heart.

What we want to do is regenerate myocardiocytes (heart muscle cells). There are a few potential sources. The best, of course, are embryonic stem cells, but they do have problems, including ethics problems. Umbilical cord blood, placental blood cells, bone marrow cells, skeletal muscle cells, and peripheral blood cells all contain some (not a whole lot) of stem cells with the potential to become myocardiocytes when properly triggered. The lower down the list, the harder to trigger them as cells lower down the list are more mature and less pluripotential. Therefore, peripheral blood stem cells are the hardest to transform into myocardiocytes, when compared to embryonic stem cells. Also, peripheral blood contain very limited number of stem cells.

It's attractiveness is the fact that it is easy to harvest (just a venipuncture), and appeal to those who have no large research laboratory to harvest the better grade stem cells. You merely take the peripheral blood cells, locate those with certain cell ligands, like CD 34 ligands, and assume that these cells can regenerate into myocardiocytes. Collect these cells and just administer them.

As they saym the devil is in the details. How do you administer them to allow regeneration at the dead heart muscle site. Most success stories seem to come from direct injection into the dead heart muscle. Injection into the main veins, are almost of no value, as insufficient amounts reach the target area, and so the targetting is very weak and almost of no value. Injecting into the artery has also proven rather ineffective. Another unintended consequence we have seen is embryonic stem cells at the dead heart muscle site, transform into bone cells (osteocytes) because of wrong triggering. We have also seen the production of all kinds of non cardiac tissue. It is very frightening (in more than a Stephen King sort of way), to have bone in the heart.

Assuming we get everything right and it is properly targetted and triggered, then the stem cells become myocardiocytes and myocardiocytes are inherently self excitable. This is a property of all cardiac cells. In our heart, this self triggering potential is channelled through a proper channelling pathway, so that they are trigger in synchrony with other cells, and so the heart contracts in-synchrony like a group of marching soldiers. Stem cells regenerated myocardiocytes don't always obey the rhythm of this march. Lone ranger type activity is potentially fatal. This had happenned mostly, but not exclusively, with skeletal muscle stem cells regenerated myocardiocytes.

Ignoring skeletal muscle stem cells we could look at peripheral blood stem cells. The most early recognised problem with peripheral blood stem cells, seem to be it's doubtful value, and angioplasty stent restenosis. The current day understanding of peripheral blood stem cells myocardial regeneration is that the stem cells induce angiogenesis and not myocardiocyte genesis. They have a high incidence of stent restenosis and recurrence of CAD. That is why, the Koreans, who lead the work on peripheral blood stem cells, could never enroll enough patients and bring the study to completion, because of the study drop-out due to coronary artery stent restenosis. Much more work needs to be done.

How do we document success in myocardial regeneration?

We need serial study of heart function, if possible regional wall motion study, by an independent laboratory. The same doctor who inject the stem cell, doing his own heart assessment and deciding his own success, is hardly scientific. The most convenient is the use of echocardiogram. However, echocardiogram is an imaging modality, and there will be inter-observer and intra-observer differences. The findings are not hard facts. There are shades of gray. Some trials use MRI scans to document regional wall motion abnormality, and also improvement. It is more hard and objective. We could also use MSCT scans. The point is that we need to scan and scanning has to be done independently.


The summary is that although all of us think that myocardial regeneration holds great promise for our patients, and stem cells hold great promise, much work clearly needs to be done. It is stillv ery early in the game. Like all good treatment regimes, we must first make it safe. Once we know that it is safe, then we must make it as effective as we can.

Remember that a guiding dictum in treating patients is Primum Non Nocere (First, do no harm). While this is falsely attributed to the Hippocratic Oath (it appears in his work title Epidemics) the full statement goes on to tell us "As to diseases, make a habit of two things—to help, or at least to do no harm."

At present it appears that stem cell therapy for the failing heart is clearly not yet ready for prime time.

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