Cardiac by-pass sans surgery
(appeared in Sep 2014)

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Micro-by-pass, which the body builds by itself, would open many doors in cardiac care, says S.Ananthanarayanan.

Heart disease, in the form of blocked coronary arteries and heart muscles starved of blood supply, which means oxygen and glucose, is a leading cause of disability and death. Surgical intervention, to create alternate paths around the blocks, is often not possible and, in any case, is fraught with risk.

An alternative possibility, which has been worked on in the last two decades, is to flood the place which has the blockage with gene and protein material which promotes the growth of new blood vessels, so that a path around the block develops without the need for a surgical, cut and splice operation. But methods to actually deliver the right quantities of carriers of these therapeutic agents where they are needed and to ensure that they stay there have been elusive.

Arun H.S. Kumar, Kenneth Martin, Brendan Doyle, Chien-Ling Huang, Gopala-Krishnan M. Pillai, Mohammed T. Ali, Kimberly A. Skelding, Shaohua Wang, Birgitta M. Gleeson, Saleem Jahangeer, Erik L. Ritman, Stephen J. Russell and Noel M. Caplice, of the University College Cork, in Cork, Ireland and Mayo Institute in Rochester, USA, report in the journal, Biomaterials, that they have tried out a way of placing cells that contain the blood vessel growth promoting gene in a mesh of metallic fibres. The mesh was moved down the artery to the site of blockage and pressed against the vessel wall using light metal springs, so that the payload in the mesh could promote the growth of new blood vessels, at the right place and in a sustained way.

Angiogenesis

Angiogenesis is name given to the creation of new blood vessels from pre-existing ones. Specific agents that bring this about, from scratch, are needed during the development of the embryo, for the formation of the circulation system. These agents then continue their work to maintain the system of veins and arteries, because less hardy blood vessels, like capillaries, suffer damage all the time. Body cells are able to recognize damage to blood vessels when they sense that the supply of oxygen that comes through blood vessels has started to drop. When oxygen supply runs low, cells are programmed to generate a family of proteins known as Vascular Endothelial Growth Factors (VEGF), which promote the growth of the endothelium, or the inner layer of blood vessels. The endothelial cells line the entire circulatory system, from the heart to the capillaries and VEGF prompt them to break free and form sprouts that can grow into new blood vessels. This action can progress at the rate of several millimeters a day and is responsible for the growth of vessels to connect gaps in the network of capillaries.

The possibility of swamping the site of an artery block with VEGF, to promote growth of blood vessels, which could form alternate paths in cardiac arteries was tantalizing, say the authors of the paper in Biomaterials. While physically taxing and hazardous by-pass surgery was so far the only option when there was near total blockage, the need now was to find a way to deliver, and retain at the site, genetic or cellular material which could generate VEGF in good quantity. Experiments carried out on animals had not been significantly successful and rapid angiogenesis often led to formation of tumours. Angiogenesis, in fact, is one of the instruments used by cancers to spread, and stopping angiogenesis is one of the strategies in treating cancers. But in trying to promote blood vessel growth for cardiac care, the problem was to control and continue the delivery of therapeutic material to the site.

The Ireland and Rochester group have devised a tiny cartridge, resembling a needle, which could be introduced into blood vessels with ‘key hole’ surgery. The device is a mesh of metal fibre, as shown in the picture, and can be fixed against the blood vessel side, at the place where required, with the help of thin springs that press against the opposite side of the vessel, but do not obstruct blood flow. This is an arrangement, called a stent, which is already in use to widen constricted blood vessels. While the mesh could thus be fixed in position, the mesh was first prepared with its payload of cells that would generate VEGF.

Generating VEGF

The trial reported in the journal is of device used in a pig heart, in an artery in which a block was introduced. The payload in the mesh consisted of soft muscle cells (SMC) taken from the pig’s own body at the time of introducing the block. The SMC was genetically engineered, by introducing the genetic code into their DNA with the help of a reverse-acting form of virus, to generate VEGF protein. The cells were cultured externally for four weeks and then introduced into the mesh, which was placed, with the help of a catheter introduced through a major artery, within the cardiac blood vessel of the pig, at the site of the block.

CT scanning, X Ray, microparticle assays, introduction of investigative catheters, tests of heart function, were carried out just before the mesh was placed, which was four weeks after the block was introduced, and again four weeks after the mesh, when the pig hearts were also dissected. Twenty eight Yorkshire pigs were used for the trial and they were divided into two groups, one which received the procedure and the other which did not, as a control group. Investigators were not aware of which group any pig they were dealing with came from.

The results are reported to show marked increase in the network of the small blood vessels that supply the walls of large blood vessels, which led to increase in the levels of VEGF protein and the formation of colonies of cells that line blood vessels. These results suggest that the procedure clearly had the potential to increase generation of new blood vessels. The procedure also markedly increased blood flow in the region and this was reflected in more efficient pumping action of the heart. “Our data indicate robust, clinically relevant angiogenesis can be achieved in a” pig heart with and artery block, which models the same condition in humans, say the authors of the paper. Further work in this procedure could lead to its use to deliver different curative substances, VEGF is not the only one, to create alternative blood paths in cases of blocked blood vessels, and without recourse to major surgery, they say.