An Oxfordshire coroner recently announced that George Michael died of natural causes. The post-mortem examination revealed that the singer suffered from a number of health problems, including dilated cardiomyopathy.
Dilated cardiomyopathy (DCM) is a disease of the heart muscle. Up to half of the cases are caused by an inherited faulty gene. By understanding the inherited form of the disease, we hope to gain insight into the mechanisms that cause DCM and improve the treatment for patients.
DCM affects about one in 2,500 people and is a major cause of heart failure. Around half of DCM patients die within five years of a diagnosis. Symptoms of the disease include fatigue, shortness of breath and swelling in the legs and abdomen. It is usually diagnosed using techniques that can image the heart and assess how well it is pumping, typically echocardiography which uses sound waves.
DCM primarily affects the main pumping chamber of the heart known as the left ventricle. The walls of the ventricle become stretched and thinned, making the heart less efficient at pumping blood. This eventually leads to heart failure where the heart is unable to supply the body with enough blood.
People with DCM are initially treated with drugs, such as ACE inhibitors and beta-blockers, to improve heart function. When the drugs become less effective, patients are sometimes fitted with an implantable device to maintain adequate heart performance. As a last resort, patients may be given a heart transplant.
There are many causes of DCM. It may come about as a side effect of infectious diseases affecting other parts of the body (such as Chagas disease), a reaction to toxins (for example, poisoning by mercury or lead) or a response to alcohol or drug abuse. In addition to these causes, DCM can also be inherited by one or both parents transmitting a mutant version of a particular gene. It is estimated that between one-third and one-half of DCM cases are inherited.
Finding the mutant genes
One of main research interests in our laboratory at the University of Oxford is the understanding of inherited DCM. We hope this will give insight as well into the acquired forms of the disease and lead to improved treatment for DCM patients.
Over the past 20 years, scientists have studied DNA from DCM patients to identify genes that cause the inherited disease. More than different genes have now been found and a single change in the DNA (known as a mutation) of one of these is enough to cause the disease.
These mutant genes produce mutant proteins that have diverse roles within the heart muscle. Broadly, they seem to affect the ability of the heart to contract and relax – vital for its role as a pump. They do so either by altering the ability of the heart muscle cells to produce the necessary energy to power the process, or by directly affecting the cellular machinery that makes the heart contract.
The mechanism of contraction involves the sliding of two sets of filaments within the heart cells – referred to as “thick and thin filaments” – and it has been shown that proteins that make up these structures are mutated in DCM patients.
Among these proteins is the main component of the thick filaments called myosin. Myosin performs the role of the motor during contraction, in that it coverts chemical energy to drive the sliding of the filaments. By comparing the ability of normal and mutant filaments to contract, it has been shown that the mutations that cause DCM generally lead to reduced force of contraction.
We believe that the inherent inability to produce sufficient contraction of the heart muscle reduces the heart’s effectiveness as a pump and is an important early trigger in the development of DCM.
New drugs are being developed to target the protein myosin in order to increase contraction – and initial drug trials are already taking place in humans. As well as being applicable to patients with inherited defects in the heart’s contractile machinery, a similar approach may also be beneficial to those with DCM due to non-genetic causes. Although these drugs are not yet available to patients, it is hoped that they will offer real benefit to people who suffer from this devastating condition.