New Hope for Growing Blood Vessels & Other Parts
Dr. Alvin Chin the distinguished pediatric cardiologist, researcher and professor of biology at University of Pennsylvania School of Medicine–and as readers of Immortal Bird know, one of my most trusted medical advisors and mentors–recently sent me an article from the Wall Street Journal that describes an astonishing development: “To Fix a Heart, Doctors Train Girl’s Body to Grow New Part.”
Doctors at Yale University were able to use an absorbable tube seeded with stem cells from a young gir’s bone marrow to create a conduit that acted like a blood vessel, enabling the single ventricle patient to get blood sent directly from her lower extremities to her lungs, where it could pick up oxygen and expel carbon dioxide. She is currently thriving. Most Fontan patients, like Damon, have a synthetic Gore-Tex tube constructed to help them get blood to the lungs but this can develop problems like clotting and infection as the patient grows. This tissue-engineered blood vessel represents a remarkable advance in regenerative medicine and holds tremendous hope for several diseases but Congenital Heart Disease (CHD) patients and their families should pay special attention, since the first successful patient was one of their own.
In addition to the article, Dr. Chin sent me his own commentary on the finding. It is dense but filled with his signature insight and sharp observation. I reproduce it here for those who are familiar with hypoplastic left heart syndrome, single ventricle and similar conditions:
“This is a story that was uploaded by Yale and featured in the WSJ. It has to do with the Stage III – the last of the 3-stage surgical palliation which most single ventricle pts currently undergo…..although Damon skipped Stage II and had only a two-stage palliation, i.e., Blalock-Taussig shunt (and repair of total anomalous pulmonary venous connection) as a newborn followed by lateral tunnel, non-fenestrated Fontan at age 4.
Most of the attrition so far has taken place at Stage I or in the time interval between Stage I and Stage II; however, over the next several decades, the most agonizing attrition will take place because of: (a) the constraints imposed by the Fontan circulatory setup created at Stage III (which is what Dr. Rodefeld’s impeller pump is trying to rectify), and (b) problems which are initiated by the long interval between Stage II and Stage III.
The time interval between Stage II (typically accomplished by 6 months at the latest) and Stage III used to be 6 months. The Stage III is accomplished using one of two approaches – “lateral tunnel” or “extracardiac conduit”. The lateral tunnel is mostly one’s own tissue, so it can be done at any age….it grows as the patient grows. So, it was frequently done at about 12 months of age.
For the last 5 to 8 years, however, the fashion among surgeons is to implant an extracardiac conduit (“it’s easier to do, we think it’s easier to get symmetrical flow to both pulmonary arteries, and we don’t have to touch the patient’s atrium”). If you perform this style operation at age 12 months, you have to use a 14 mm Gore-Tex tube. Since the diameter of an adult vena cava is typically ~20 mm, a 14 mm Gore-Tex tube will have to be replaced later on. So what surgeons decided to do is to wait until the pt is ~3 or 4 when the larger size of the pt will allow the use of a 20 mm Gore-Tex tube. There hasn’t been much pushback from cardiologists because the prevailing view is that the Fontan circulatory setup is an unmitigated disaster, so the longer you can wait to perform the Stage III (Fontan), the older the pt will be before needing a transplant. [Note: I am not persuaded that we yet have a sufficiently rigorous understanding of how the Fontan circulatory setup affects individual patients to deem it “a disaster”, and we certainly have only begun to explore ways of optimizing the performance characteristics.]
The problem with this approach is that during the time a pt is maintained with Stage II, major aorto-pulmonary (A-P) collateral arteries develop. Between 10 and 50% of the blood ejected by the Ventricle winds up in these A-P collaterals (think of them as many tiny BT shunts….individually they don’t look like much, but add them all together and they divert away a significant percentage of the blood the ventricle is trying to pump out to the body). We don’t know what the stimulus is for their growth; it may be the lower-than-normal pulmonary blood flow inherent in Stage II, it may be the lower-than-normal pulsatility of flow in the pulmonary arteries inherent in Stage II; etc.
The volume overload the A-P collaterals place on the single ventricle frequently injures the ventricle. One might argue that it’s possible that a single ventricle pt’s lone ventricle isn’t normal and that it’s that inherent abnormality that we have to worry about. We can’t settle that argument yet. However, even if it is abnormal to start with, we really shouldn’t be doing things to it which will just shorten its effective lifespan.
We also have no idea what the A-P collateral flow is doing to the pulmonary microvasculature over a 3-year period (between age 6 months and age 42 months). The two most important determinants of the cardiac output after Stage III is completed are: how pristine the pulmonary vasculature is; and the performance characteristics of the Ventricle.
That’s where the Yale group’s experiment comes in. You can theoretically do this style of Stage III at age 12 months, since it’s essentially a pt’s own cells seeded on to a bioabsorbable scaffold. It should grow as the pt grows. Moreover, using MRI and computational flow dynamics, you could produce a computer-designed “optimized” 3-D conduit shape (i.e., lowest power loss, highest chance of distributing flow symmetrically to the pulmonary arteries). Then, if you had a way of fabricating the scaffold the way people are now using 3-D printing to fabricate all kinds of complex components, then you could do the Yale procedure with a personalized scaffold rather than just a standard straight cylindrical scaffold (as shown in their video).