Therapeutic angiogenesis is an experimental area of treatment for cardiac ischemia, which is a common symptom of coronary artery disease. Cardiac ischemia, the primary symptom of which is angina, is usually a temporary situation in which the heart does not get enough oxygen. This lack of oxygen is often due to a blocked or obstructed coronary artery in the heart,  usually due to atherosclerosis, or "hardening of the arteries." Angiogenesis is the process by which new blood vessels are formed, often in response to injury. In some cases of coronary artery disease, new blood vessels form to continue supplying the heart with oxygen-rich blood, despite the presence of widespread disease and blockages in the main coronary arteries. These new blood vessels are called collaterals.

The field of therapeutic angiogenesis is founded on the idea of stimulating the growth of collateral blood vessels on the heart. It is hoped that the new vessels will increase the amount of oxygen-rich blood reaching the heart muscle (myocardium). When the heart muscle is not receiving enough oxygen-rich blood, the person may suffer from chest pain or even a heart attack.

Although more research is necessary, some researchers hope that therapeutic angiogenesis may one day offer the benefits of a bypass without the open-heart surgery.

Derived from the words angio (blood vessels) and genesis (creation), angiogenesis is the creation of new blood vessels. This process occurs naturally under certain circumstances, such as the healing of a cut. Therapeutic angiogenesis is an experimental treatment that medically promotes the creation of new blood vessels.

In oncology (the study of cancer), anti-angiogenesis treatments have shown promise because they prevent the growth of new blood vessels that feed tumors. In cardiology (the study of the heart), angiogenesis has shown promise in growing new blood vessels to increase the flow of blood to the heart. For people whose coronary artery disease is so advanced that bypass surgery would be of only limited benefit, therapeutic angiogenesis may offer an alternative.

The therapy is also being studied for use in patients after surgery or such catheter-based procedures as balloon angioplasty. Many of these patients still experience symptoms of heart disease even after treatment because of incomplete blood flow. Therapeutic angiogenesis offers the promise of restoring these patients to a symptom-free state. 

Whether used in patients before or after surgery, the goal of therapeutic angiogenesis in the heart or peripheral arteries (e.g., peripheral artery disease) is to increase blood supply to the muscle. In most cases, this blood supply is constricted because of plaque that has built up in the arteries, the result of a disease process known as atherosclerosis. This plaque may result in the blockage of blood flow, resulting in cardiac ischemia when the heart demand increases as during exercise. Cardiac ischemia may result in either chest pain (angina) or no symptoms at all (silent ischemia).

Over time, episodes of cardiac ischemia can become longer, more severe and may become dangerous. A worsening of cardiac ischemia generally means that the underlying coronary artery disease is worsening, and the flow of blood to the heart is gradually reducing. In severe cases, this may result in a heart attack or a permanent weakening of the heart muscle that leads to an enlarged or deformed heart (ischemic cardiomyopathy).

Therapeutic angiogenesis is designed to promote the growth of new (collateral) blood vessels that are free of plaque and other blockages. These new blood vessels can deliver much-needed oxygen to the heart and help to avoid future episodes of cardiac ischemia or help improve blood flow after a surgical procedure or minimally invasive intervention such as balloon angioplasty.

Recent clinical studies of therapeutic angiogenesis have failed to decisively conclude that the therapy is effective, however many researchers believe the technique will one day prove useful. The possibility of side affects associated with the treatment remains a concern and the most efficient delivery method for the therapy remains in dispute. More research and testing are required before this therapy is pronounced effective by the wider medical community.

Promoting the growth of new blood vessels through therapeutic angiogenesis may be accomplished through the use of one of the following:

The first strategy is the use of one of the body’s natural growth factors (angiogens). Growth factors are hormones that produce enormous changes throughout the developmental process from the moment of conception, through puberty, to adulthood. Among the changes caused by growth factors is the formation of new blood vessels.

Specific growth factors that are being investigated for their angiogenic effects are basic fibroblast growth factor (bFGF), fibroblast growth factor (FGF), platelet-derived growth factor (PDGF) and vascular endothelial growth factor (VEGF). Of these, FGF and VEGF have been studied the most widely.

Lab studies are showing that growth factors yield positive results when the tissue is continuously exposed to the growth factor for a period of more than a month. As a result, researchers are experimenting with delivery methods, including gene therapy and protein delivery, or direct injection of the growth factor(s). Each appears to have advantages. For example, delivery by protein allows for more precise dosing and avoids the potential problem of introducing foreign DNA into the body. However, proteins tend to have a short half-life, meaning that multiple doses may be necessary. On the other hand, gene therapy allows for long-term production of the growth factor at the target site, requiring only one dose.

To understand gene therapy, and how it is used to delivery growth factors, it is necessary to understand how genes work. In the center of every human cell are 46 chromosomes. Each chromosome contains long, tightly wound strands of DNA (deoxyribonucleic acid), which carry the genetic blueprint for how the human body is constructed and maintained. The DNA blueprint for the body is written in a language that scientists are learning to read. They have identified segments of DNA that occupy a specific location on the chromosome and have specific effects on the body (e.g., manufacturing a protein). These DNA segments are called genes, the basic units of heredity.

In traditional gene therapy, genes that stimulate the production of growth factor are coded into a vector, which is a piece of genetic material from another source (e.g., a virus). This genetic material is introduced into the target tissues, which "turns on" the native genes and stimulates them to produce the coded growth factors. In addition to viral vectors, researchers are also studying nonviral vectors, such as plasmid DNA and liposomal complexes.

At this point, research into growth factors is still highly experimental and the results in human subjects have been somewhat contradictory. Currently, growth factor-derived therapy is reserved for patients who have not responded to conventional therapies, such as bypass surgery or balloon angioplasty.

One area of gene therapy that has received significant attention is the use of stem cells. In this case, genes are not used as a delivery system. Rather, scientists attempt to implant immature stem cells into damaged tissue, hoping that the stem cells will grow (or differentiate) into mature heart muscle or artery cells. This is possible because the immature stem cells have the ability to develop into a variety of mature cells, such as red or white blood cells, platelets, etc.

In various studies, physicians have attempted to transplant a patient’s own stem cells from their bone marrow into the heart after a heart attack. The hope is that these immature bone marrow stem cells will mature into new cardiac muscle to replace the damaged muscle. Results from these trials, however, have been mixed. In some studies, the stem cells failed to mature into new cardiac muscle, while others have shown some improvement.

For heart failure patients, bone marrow cells have been injected into the heart’s left ventricle. Bone marrow cells are seen to enhance the formation of blood vessels and rebuilding of muscle. Early results have been promising, with some study patients responding so well that they were taken off waiting lists for heart transplantation. Other researchers are seeing that bone marrow-derived stem cells implanted into the leg can impact against peripheral arterial disease.

The second strategy involves the use of chemicals that stimulate the production of growth factors. One example is hypoxia-inducible factor 1 (HIF-1), which is a naturally occurring chemical that is produced when the heart experiences a lack of oxygen (hypoxia) during cardiac ischemia. HIF-1 stimulates the production of the growth factor VEGF, which stimulates the growth of new blood vessels (collaterals) to the heart. Because production of HIF-1 appears to be a natural reaction of the body, researchers have been studying its use as a medical treatment.

The third strategy for promoting the growth of collateral blood vessels is the use of medications that mimic the effects of growth factors. For example, one animal study compared the angiogenic effects of a growth factor (VEGF) and a certain drug used to treat high blood pressure. Although the medication was not as effective as the growth factor, it still yielded a significant result. Further research is needed to understand how this medication was able to stimulate angiogenesis and what other medications might be able to do the same thing.

The fourth strategy for promoting angiogenesis is a procedure called transmyocardial revascularization (TMR). In this procedure, a laser beam is used to form up to 40 small holes, or channels, in the heart muscle (myocardium) of the left ventricle. The laser may be introduced to the body either through surgery or via a catheter that is fed through the femoral artery in the groin and all the way up to the heart. The exact mechanism by which TMR increases blood blow is not completely understood. It may function by stimulating new blood cells, or it may work by destroying nerve cells, thus stopping the patient from feeling any pain. This procedure is approved by the U.S. Food and Drug Administration for patients with severe angina who lack other treatment options. So far, in large, clinical trials, it has shown short-term benefit, but there are no long-term studies to see how TMR fares over the course of many years. A randomized trial of percutaneous catheter directed TMR from the femoral artery showed no benefit. TMR is still used at the time of CABG if some areas of the heart do not have adequate arteries for bypass.

Therapeutic angiogenesis is difficult to clinically evaluate, because a patient who makes certain lifestyle changes (specifically exercise) and regularly takes medications can stimulate the growth of collaterals without additional therapy. Clinical testing has found it challenging to differentiate between the positive effects of therapeutic angiogenesis and the positive effects experienced by those individuals in a controlled placebo group.

There are a number of different methods for introducing the growth factors, hypoxia-inducible factor 1 (HIF-1), genes or medication into the body. They include:

The best method of delivery remains a significant issue. For example, when growth factor-carrying genes are introduced into the general circulation, there is the possibility they can stimulate cancer calls to grow because cancer growth relies on the creation of new blood vessels. On the other hand, there is a risk involved with direct injection into the heart muscle. Currently, researchers are working to understand the best delivery methods and dosing schedules for the various forms of therapy. Some researchers believe that optimal therapeutic angiogenesis may rely on several different approaches, including various growth factors delivered through different methods.

In 1999, researchers from Harvard University began to study the effects of implanting 10 microcapsules into the heart wall during bypass surgery to spur the growth of new blood vessels. The microcapsules released growth factor slowly over the next four to six weeks, with promising results. Further research is needed to understand the potential use of microcapsules in therapeutic angiogenesis.

At this point, researchers are guardedly optimistic that therapeutic angiogenesis could be used for bypass candidates for whom surgery alone would not offer enough improvement in blood flow, or in people for whom surgery did not relieve all their symptoms. Some researchers are hoping that therapeutic angiogenesis may one day offer the benefits of a bypass without the open-heart surgery. There is also cause for optimism regarding heart failure and cardiomyopathy. 

However, despite positive developments in the early 1990s, therapeutic angiogenesis remains highly experimental and many techniques that were tested on animals did not translate well into human subjects. Additionally, some concerns have been raised about the use of growth factors in therapeutic angiogenesis. They may:

It is important to note that none of these fears have come to pass in the hundreds of human participants that have tried the treatment so far and it seems like a safe approach so far. All candidates are carefully screened to see if they are vulnerable to any of the above complications.

This is still an experimental procedure and more research still needs to be done. However, therapeutic angiogenesis is showing significant potential as an effective strategy for treating cardiovascular disease without surgery.

Preparing questions in advance can help patients to have more meaningful discussions with their physicians regarding their conditions. Patients may wish to ask their doctor the following questions related to therapeutic angiogenesis:

1. Is therapeutic angiogenesis a technique that could be used on me?
   
   
2. How could this therapy effectively treat my condition?
   
   
3. Are there any other alternative therapies available to me that may achieve the same results?
   
   
4. Could surgery be effective at reversing my condition?
   
   
5. Could therapeutic angiogenesis be available for me to use in the future? How long would I need to wait?
   
   
6. Is it possible for me to become involved in a clinical study of therapeutic angiogenesis?
   
   
7. Could lifestyle changes help improve my condition?
   
   
8. Are there any medications available that could improve my condition?
   
   
9. Do the risks associated with therapeutic angiogenesis make it unlikely that I will ever be able to use it as a treatment?
   
   
10. Does this therapy involve the use of embryonic stem cells?