Diseases

Atherosclerosis

Atherosclerosis is the process where fatty deposits in the arteries gradually cause them to become blocked. This leads to heart attacks, strokes, dementia and other serious conditions. Pharmaceutical research has led to medicines that reduce blood lipids (fats). These have saved the lives of millions. It is expected that further research will lead to even more effective treatments.

What is atherosclerosis? Top

Sometimes called atheroma or arteriosclerosis, it is a degeneration of the arterial wall characterised in its early stages by fatty deposits (plaques) on which blood clots can form and later by thickening of the walls of the arteries and restricted blood flow.

Plaque in the coronary artery will lead to the dysfunction of the lining of the arteries and predispose people to angina pains and heart attack, while plaque in the neck and head increases the risk of cerebrovascular disease such as pre-senile dementia and stroke.

Plaque may also affect the limbs and cause peripheral vascular disease. Plaques are of concern because they increase resistance to blood flow, forcing the heart to work harder, contributing to raised blood pressure and heart failure. They also reduce the delivery of oxygen to vital organs, thus precipitating serious circulation problems, and act as sites for blood clots which may detach and cause acute blockage in veins and arteries.

Plaque formation starts very early in life. Signs of it (called ‘fatty streaks’) are found even in the main arteries of three year-olds, and more than three quarters of soldiers killed in battle at an average age of 22 had extensive plaques. So it would appear that plaque occurs in all of us, but it is the degree and rate of formation that are important.

Various theories exist to explain why plaques form. One theory presumes that it is a response to injury to the vessel wall by factors such as excess cholesterol, chemicals in cigarette smoke, raised blood pressure or diabetes. Certainly, a close correlation exists between these factors, age and the percentage of artery wall covered by raised plaques.

Who does atherosclerosis affect? Top

The blockage of blood vessels by plaque or blood clots is a major cause of illness and death in the European Union, where cardiovascular disease accounts for around 40 per cent of deaths.

 

 

 

 

Diagrammatic cross section of a healthy and an atherosclerotic artery

Present treatments Top

A healthy lifestyle will help control plaque formation - as will the treatment of related conditions. Cholesterol and triglyceride levels can often be controlled by dietary measures, but some people have difficulty adhering to such diets, or have an inherited tendency towards high levels of blood cholesterol, and require active therapy. The main classes of medication to control cholesterol level are bile acid sequestrants, fibrates and statins.

Bile acid sequestrants have been available for almost 30 years. They work by binding to and removing bile acids from the gut during digestion. As the body synthesises more bile acids, cholesterol in the blood is consumed and a fall of 15 to 30 per cent may be achieved. However, absorption of the fat-soluble vitamins A, D, and K is also reduced and circulating levels of many other medicines given at the same time can be affected, which may lead to dosage problems.

The fibrates appear to act by modulating the lipid balance in the blood. Over a period of time, a five to 15 per cent reduction in cholesterol level has been demonstrated. Several are used to treat at-risk patients whose raised lipid levels are resistant to diet and other medication.

The most prominent class is the statins. These block the enzyme HMG-CoA reductase; a key step in cholesterol synthesis, reducing levels by 30 per cent or more. As experience with these medicines is built up, it is becoming clear they may confer many clinically significant benefits beyond their primary indications.

The newer molecules have been shown to produce greater reductions in low density lipoprotein cholesterol than the earlier medicines. Recent trials suggest that these compounds may be able to reduce the risks of strokes or a second heart attack. Authorisation still needs to be granted for these new expanded indications in cardiovascular disease.

Meanwhile, scientists have discovered variants in the HMG-CoA reductase gene that may explain the variations in the efficacy of statins within the population. The research could also have implications for the use of pharmacogenetics to identify which patients might best respond to therapy. Such research could lead to the tailoring of treatment with medicines to individual genotype, and improve the safety and efficacy of commonly used compounds.

Inhibitors of the enzyme acyl-CoA:cholesterol acyltransferase (ACAT) are a new type of anti-atherosclerotic therapy. They show a rapid reduction in triglycerides and low density lipoprotein cholesterol. Another molecule inhibiting cholesterol uptake from both dietary and biliary resources in the intestine is available as a single therapy or in a fixed combination with a statin as an adjunct to diet in patients with primary hypercholesterolaemia.

What’s in the development pipeline? Top

A new approach is a compound that prevents the splitting from low-density lipoprotein (LDL) of a substance that is thought to trigger the inflammatory process in the early stages of plaque formation.

High-density lipoprotein (HDL) is believed to protect against atherosclerosis by removing cholesterol from the vessel walls and transporting it to the liver for elimination. The major protein component of HDL is apolipoprotein A-1. Clinical trials are in phase 3, as is a complex of a 22-amino acid peptide and lipids which mimics the biological properties of ApoA-1.

In addition, research is exploring so-called ‘PPAR modulators’. Another new class of compound, inhibitors of microsomal triglyceride transport protein (MTP), is also being investigated in Phase 3 clinical trials.

Recently, researchers reported on a series of orally active compounds with dual action to reduce both LDL and lipoprotein(a), two independent risk factors for cardiovascular disease. Another series of molecules is designed to elevate low levels of HDL, which is believed to lead to the halting of the atherosclerotic process.

In 2007, angiotensin-converting-enzyme (ACE) inhibitors that are used to treat hypertension have been shown not only to reduce cardiovascular mortality and morbidity in patients with heart failure or left ventricular systolic dysfunction (LVSD), but also to reduce serious vascular events in patients with atherosclerosis without known evidence of LVSD or heart failure.

Another option with potential in the prevention and treatment of vascular disease may be the further development of phosphodiesterase 4 inhibitors. Scientists are looking for compounds that can reduce the proliferation of smooth muscle cells involved in atherosclerosis.

The longer-term future: Top

The progress in understanding of the process of atherosclerosis has stimulated the development of new agents that act directly on other components of plaque than lipids. ACAT inhibitors are one example of compounds that act directly on the sequence of events in plaque formation.

Men experience a more rapid progression of atherosclerosis, but the basis for this gender difference is not clear. A substance called prostacyclin PGI 2 prevents processes associated with the formation of atherosclerotic lesions, and the protective effect of estrogen in women may be via stimulation of PGI 2 production.

Pre-clinical research suggests that oestrogen acts through the oestrogen receptor subtype to generate PGI 2. Female mice lacking a receptor for PGI 2 develop atherosclerosis as rapidly as male mice. This mechanism may be of interest in developing new therapeutic approaches to protect men from developing atherosclerosis.

The intention in the future is to design medications that not only slow the progress of atherosclerosis, but maybe even reverse it.