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The deadly combination

Heart disease is the number one killer in the Western world. For example, despite all the recent advances in clinical practice, approximately 50% of all men die of cardiac disease, that is, one in two of all males reading this article. The underlying anatomy is simple: the heart is a muscular pump that delivers blood to the entire body via the aorta. The first vessels to branch off the aorta are the two coronary arteries, which supply the heart muscle with oxygenated blood. Reduce the flow and the patient feels the pain of angina as the heart muscle struggles with an inadequate oxygen supply. Stop the flow and the heart muscle dies (heart attack). These two scenarios occur when the coronary arteries are narrowed or blocked by atherosclerosis, which an extremely common disease because of Western lifestyles and diet. Nearly half of all heart-attack patients die in the first 24 hours. The remainder have permanent damage to their hearts. The dead muscle becomes scar tissue, which can no longer contract, therefore, the remaining muscle cells have to work harder to compensate. If too much muscle is damaged, the demand placed on the remaining cells results in them becoming overworked and dying, thus compounding the problem leading to heart failure and death. This detail serves to highlight that it is both blood supply and cardiac muscle that are important, not just one or other, and both need fixing. This article discuses possible regenerative-medicine solutions to tackle the multicomponent nature of restoring a damaged heart.

The plumbing

Traditionally, there have been two approaches to restoring blood supply to the heart: medication and intervention. For example, each year more than one million coronary artery bypass grafting (CABG) procedures are performed on patients who have the severest of atherosclerotic disease. The operation requires the harvesting of a vein from the leg, which involves an incision from groin to ankle, often on both legs. The patient’s chest is then opened and the vein from the leg is used to bypass the diseased sections of the larger coronary arteries. The drawbacks to this approach are numerous and include the requirement for an extra operation to harvest the vessel(s) and the associated increased complications. However, the biggest drawback is that the vein in the leg is from a low blood pressure environment and when plumbed into the high-pressure circuitry of the coronary arterial tree, its functional life is short. This results in the procedure needing to be redone often in less than 8–10 years. Demand for alternative plumbing material is therefore high, even higher if one factors in the 50–100000 Americans who die each year because they lack suitable vessels to transplant, for example, because of previous varicose-vein surgery. Synthetic materials and cadaveric vessels have all been tried and found to be mainly unsuccessful.

The laboratory alternative

A possible alternative is to grow vessels in the laboratory. A number of tissue engineering companies have approached this problem including Organogenesis (Canton, Massachusetts, USA, www.organogenesis.com), Advanced Tissue Sciences (La Jolla, California, USA) before it was acquired by Smith and Nephew (London, UK, www.smith-nephew.com) and Cytograft (Novato, California, USA, www.cytograft.com). Cytograft’s novel fabrication process requires a postage-stamp-size skin biopsy to provide the living cells (fibroblasts). These cells are expanded in number in the laboratory to form a thin sheet that is then carefully wrapped around a mandrel to produce a living tube of cells. The company has conducted preclinical studies and in its first clinical trial, nine patients have been enrolled in a pilot study in Argentina for a less-severe condition. A second trial with 25 CABG patients has already been approved in the United Kingdom (UK).

A cardiac patch

Size is one major drawback to tissue engineering vessels in the laboratory and then surgically plumbing them in. Submillimetre vessels are unworkable. There is, therefore, a demand for an alternative technology to create the smaller diam-eter vessels in vitro. Enter Anginera, a cardiac patch containing living cells, which in preclinical testing has demonstrated the ability to trigger small coronary vessels to regrow (angiogenesis). Anginera was developed by Advanced Tissue Sciences as a progression of its Dermagraft skin product. After the company filed for Chapter 11 bankruptcy protection in October 2002, the rights to Anginera were sold off to Iken Tissue Therapeutics (San Francisco, California, USA), now acquired by Theregen (www.theregencompany.com), which is actively developing Anginera with promising results in mouse and dog models.

Restoring the pump

Not so long ago, every medical student learnt that cardiac muscle could not restore itself. However, today, cardiac muscle has been shown to have a capacity to regenerate albeit at an extremely low capacity. How the regeneration process works is not yet understood. For example, is it due to cells that reside in the heart or do the cells arrive from elsewhere via the blood stream? However, this lack of knowledge is not preventing cardiologists and cardiac surgeons from deploying various cell-based techniques to enhance the heart’s limited regeneration capacity. The rationale being that most patients with severe cardiac failure are dead within the year. Two approaches have been adopted, both of which deploy the patient’s own cells.

Bone-marrow cell injection

The first approach is to remove bone marrow from the patient. Bone marrow is the body’s reservoir for adult stem cells known as mesenchymal stem cells. In mice it has been convincingly demonstrated that hearts damaged by experimentally induced heart attacks can be substantially regenerated by injecting bone marrow cells into the heart muscle.¹ Trials in humans started shortly after, mainly in Germany, and now more recently in the United States and UK. However, the results so far have been less impressive than in the original animal experiments.² To date, the bone-marrow source of cells has been largely adopted by academic clinical groups and has not transferred to the commercial sector.

Muscle progenitor cells

The second approach is to use regular (skeletal) muscle progenitor cells, which are found in our propulsion muscles (that is, not cardiac muscle) and have the role of regenerating damaged muscle. Pioneering studies by Dr Phillippe Menasche, a heart specialist in Paris, started the activity in this area.³ The approach involves taking a biopsy from the thigh muscle, extracting the skeletal muscle progenitor cells, growing them in number and then implanting them into the patient’s failing heart. Early studies suggested that this technique improved the pumping power of severely damaged hearts and significantly improved the patient’s lives. This approach was adopted by Genzyme Biosurgery (Canton, Massachusetts, USA, www.genzymebiosurgery.com), which in partnership with Medtronic (Minneapolis, Minnesota, USA, www.medtronic.com) is funding a 300-patient trial across Europe, the Myoblast Autologous Graft in Ischaemic Cardiomyopathy trial. A similar approach has been adopted by other biotechnology companies, including Bioheart (Sunrise, Florida, USA, www.bioheartinc.com) and Mytogen (Charlestown, Massachusetts, USA, www.mytogen.com) with its MyoCell trial.

To date, it is too early to tell which, if either, of the above approaches will be successful. For example, in the Genzyme Biosurgery/Medtronic trial and the Bioheart trial recruitment is still underway, and Mytogen is still at a much earlier stage in its product’s development. Alternative cell-based therapies have been suggested including a number based on the use of human embryonic stem cells. For example, ES Cell Intl (Singapore, www.escellinternational.com) is planning to obtain the necessary regulatory approval in order to initiate clinical trials in 2007.

Combination therapy

Because cardiac disease is a deadly mixture of lack of oxygenated blood being delivered to the muscle cells and scar tissue instead of healthy pumping muscle, potentially curing both conditions would be of great benefit to the patient. Thus, combining the ability to tissue engineer the larger coronary artery replacements in vitro, trigger new small vessel growth in vivo and replenish the cardiac muscle cells using cell therapy will in the future undoubtedly give the cardiac specialist a fantastic arsenal in the battle to fight heart disease. Will this approach be so highly successful it knocks cardiac disease off the pedestal as the “number one killer”? Only time will tell.