Case study: Fighting heart failure
Manchester scientists are looking at genes in the heart in order to seek a treatment for the effects - and perhaps also the causes - of heart failure.
One million people in the UK currently suffer from heart failure - and, considering that it is particularly prevalent in elderly people, the figure is set to rise even further given our ageing population.
That said, the medical community is getting ever better at treating many of the conditions that lead to heart failure, including high blood pressure, heart attacks and diabetes.
As Dr Elizabeth Cartwright from the University’s Institute of Cardiovascular Sciences says: "Far more people are now surviving heart attacks, which is obviously a good thing. But this also means these people are living with a damaged heart, and that creates its own complications in terms of treatment."
She says the heart is very good at adapting to new situations, but in people with damaged hearts or high blood pressure the heart is having to work that much harder to pump blood around their bodies. This means their hearts enlarge, just like any muscle that is used a lot.
"This is fine for a while, but eventually the heart can no longer cope with this extra workload and is unable to contract and relax normally, which can lead to heart failure. When cells in the heart die they are not replaced, because the heart does not have an efficient in-built repair mechanism."
Looking at genes
Dr Cartwright and her colleagues are using recent advances in our knowledge of gene expression to identify what happens to genes in a normal heart compared to a damaged heart, in order to address the challenges for damaged hearts in terms of treatment.
"In a heart there are lots of genes doing lots of different things," says Dr Cartwright. "We are interested in looking at what particular genes are doing in particular situations."
She says that lots of harmful genes have been identified, but it is then a question of finding treatments that can specifically target those genes when they are being harmful just to the heart.
"One of the big problems is that some genes which are harmful to the heart actually have beneficial effects elsewhere in the body. So the danger is that if you target these genes in the heart, they then have a detrimental effect on the rest of the body."
To study the mouse heart, we use the same tests and investigations that would be used by a GP and cardiologist, such as measuring blood pressure, ECG, and viewing the beating heart by ultrasound scanning. These tests allow us to visualise the structure of the heart and the way it contracts and relaxes.Dr Elizabeth Cartwright / Senior Lecturer in Cardiovascular Medicine
Studying animal hearts
Dr Cartwright says that, although there are aspects of the research in terms of isolated cells that can be done in a petri dish which complement and enhance research involving animals, for more successful outcomes you need to look at the complex interaction with other parts of the body, which can only be done by turning to research involving animals. In particular, the mouse’s heart has virtually the same structure and same vessels as a human.
Dr Cartwright says: "If you scaled the mouse’s heart to the size of a human heart, you would hardly notice the difference. The only real difference is the fact that the mouse’s heartbeat is about 650 per minute, roughly 10 times as fast as a resting human heart. As such this is a robust system to use for research.
"To study the mouse heart we use the same tests and investigations that would be used by a GP and cardiologist such as measuring blood pressure, ECG, and viewing the beating heart by ultrasound scanning. These tests allow us to visualise the structure of the heart and the way it contracts and relaxes."
The fact that the mouse’s genome is also widely known is another key factor. Scientists can genetically modify mice to see the effect of taking particular genes out of the animal as they look at gene pathways.
As Dr Cartwright explains: "We are able to identify what single genes are doing, and look at specific gene pathways. We can then work towards treatments that look at the impact on the whole pathway of genes. For example, we can look at those genes that cause growth and enlargement of cardiomyocytes, the heart muscle cells."
One area of our work that we are really excited about has shown that if we delete a particular gene ... from the mouse, then those animals are protected from the damaging effects of high blood pressure on the heart and they do not develop heart failure. We have now identified a drug that has the same protective effect.Dr Elizabeth Cartwright / Senior Lecturer in Cardiovascular Medicine
Towards treatment and prevention
Dr Cartwright says the ultimate goal is to identify those genes where, if you can inhibit their activity, it will then stop the damaging effects of heart failure.
"One area of our work that we are really excited about has shown that if we delete a particular gene - PMCA4 plasma membrane calcium ATPase 4 - from the mouse, then those animals are protected from the damaging effects of high blood pressure on the heart and they do not develop heart failure.
"We have now identified a drug that has the same protective effect. When injected into the mouse, the drug inhibits the activity of the gene and prevents the mouse from developing heart failure by preventing the damaging effect of the enlargement of the heart muscle cells."
She adds that the work is ultimately moving towards treating the causes, rather than the symptoms, of heart failure.
"We are trying to really understand what is happening at the molecular level, and what impact it has on particular cells and what they are doing, and then what impact it has on the whole heart."