Every two minutes, someone in the UK has a heart attack. In 2002, 28 000 people in the UK had heart bypass surgery and a further 45 000 had surgery to open blocked coronary arteries. These techniques are now well established, but new approaches may delay or avoid altogether the need for surgery.

Preventing artery narrowing

Atherosclerosis is the main cause of coronary heart disease. It occurs when fatty deposits known as atherosclerotic plaques build up on artery walls. The narrowed arteries prevent blood circulating efficiently and starve tissues of blood. Severe lack of oxygen kills heart muscle cells and results in heart attacks (myocardial infarction).

Many treatments for heart disease slow or prevent artery narrowing and blockage in an attempt to prevent heart attacks. An old favourite, aspirin, slows artery thickening by preventing platelets – a component of blood–sticking together to form clots.

In recent years, cholesterol, a major contributor to atherosclerosis, has become a target for treatment. Statin drugs reduce the amount of cholesterol in the blood and have revolutionised treatment of atherosclerosis. Reports from the USA suggest they have reduced levels of disease by as much as 40 per cent. Statins work primarily by inhibiting an enzyme (HMG-CoA reductase) that forms part of the cholesterol synthesis pathway in the liver.

Plaque build-up in arteries involves a complex series of biological changes. As we discover more about these changes, so more targets for intervention are being identified.

Preventing cell death

But it is the damage to heart tissue that is the real killer. In general, heart muscle cells – cardiomyocytes – are not replaced when they die, so most damage to the heart is irreversible.

Some of the damage is due to apoptosis, or programmed cell death, of cells in the blood vessel walls. This process can be triggered by a variety of factors including hormones, inflammation and oxygen starvation. Cell death is a problem as it can cause plaques to become unstable, increasing the likelihood that vessels will become blocked.

A major challenge is to find out how apoptosis is regulated in vascular cells, so that therapies can be developed to inhibit this process. One important set of targets is the caspase family of proteases (enzymes that digest proteins), which are central to a cascade of reactions that eventually lead to death of the cell. Blocking this cascade can keep cells alive even when they are instructed to die. Already, trials are underway in the USA to test caspase inhibitors in patients with liver disease. The hope is that they may eventually be used to treat heart disease.

Blocking cell death is a potentially risky strategy, as it can create ‘immortal’ and potentially cancerous cells. The good news is that cardiomyocytes and cells in blood vessel walls in general do not divide, so inhibiting their death should not promote the uncontrolled cell division associated with cancers. Also, efforts are concentrating on short-term inhibition of apoptosis, confining effects to a local area.

Gene therapy

Other approaches to limiting artery narrowing include gene therapy. The idea here is to deliver a gene to affected cells; the gene directs the production of large quantities of a beneficial protein to remedy the medical problem.

Gene therapy has floundered in recent years, due in part to the death of a teenager in a US gene therapy trial, but thanks also to technical difficulties. Actually getting active genes into cells is proving very difficult.

Nevertheless, researchers have persevered with the technology and a biotechnology company – Ark Therapeutics Ltd – founded by a group of scientists at University College London hopes to be the first to market a gene as a therapeutic agent. The Ark Therapeutics’ system employs an adenovirus vector (a modified, harmless common cold virus) to deliver the gene to the damaged site. Adenovirus vectors have been used successfully in cancer gene therapy.

The company is testing a gene construct that carries the gene for vascular endothelial growth factor (VEGF), a protein involved in blood vessel growth that also protects adult blood vessels against damage. The therapy is being tested in 200 people undergoing haemodialysis in the USA. Surgeons join an artery and vein by a graft, creating a loop to which the haemodialysis equipment is attached. The join of the loop and the vein suffers damage similar to that seen in atherosclerosis. The gene therapy vector is being delivered to the site via a biodegradable reservoir inserted at the time of surgery. If the trial is successful, and the arteries are protected from narrowing, the gene therapy could potentially be used to treat patients with heart disease.

Stem-cell therapy?

Stem-cell biology is one of the most exciting areas of medical research – and researchers are already testing its potential in heart disease.

Stem cells are uncommitted cells with the potential to develop into a variety of cell types. They can be obtained from very early embryos (embryonic stem cells) but also from adults, in tissues such as bone marrow, where new cells continue to be generated in adult life.

Several years ago studies in animals showed that injecting stem cells from bone marrow into damaged hearts could repair and improve heart function. These findings have led to a series of small clinical studies. Patients with heart failure, for whom the only option is heart transplantation, have been given preparations of their own bone marrow stem cells, taken from a bone in the thigh and directly administered to the heart via a catheter. The same treatment for heart attack improves heart function.

Although highly promising, stem-cell therapy has only been tried in small groups. A European taskforce has recently been set up, chaired by Professor John Martin, to coordinate a large multinational trial. But not everyone is convinced that further trials should go ahead, because it is not yet clear exactly how the stem cells improve heart function and the full impact of injecting stem cells is not known.

Some groups have tried using muscle cells from elsewhere in the patient’s body. This too has met with some success in small clinical trials, although arrhythmias tend to occur in the week after surgery.

Using a patient’s own bone marrow cells does not create the same ethical dilemmas as using stem cells derived from embryos, and there is no risk of tissue rejection. However, adult stem cells may not be as versatile as those from other sources, which may provide greater improvements in heart function. This is currently the topic of much research and debate.

These and other technologies are offering some hope that the life of the heart may be extended. The need is certainly there: currently more than half of all patients with heart failure die within five years of initial diagnosis.

See also

• Limiting damage from lack of oxygen
• Scientists in cardiovascular harmony
• Genes that control the asymmetry of the heart
• The virtual heart
• The heart in Greek medicine and philosophy

External links

• Ark Therapeutics Ltd