Case study: Researcher V

Research: Understanding why the heart fails, as well as the effect of exercise and diet on heart disease and diabetes.

Animals used: rats

Researcher V (prefers to remain anonymous): ‘We’re interested in why the heart fails. Heart disease is still the biggest killer in the Western world, and it’s getting worse. What’s more, we still don’t know the changes that occur in heart failure.

‘We’re also interested in the effect of exercise and diet on heart disease and diabetes.

‘We mostly use magnetic resonance imaging (MRI) techniques to look at both human patients and rodents because we can see the function of the heart and any changes in its metabolism non-invasively, ie without affecting, operating on, or harming the patient or animal.

‘The heart normally uses around 70% fatty acids and 30% glucose (a sugar) as its energy source. Parts of the heart cells called mitochondria burn up this fuel with oxygen to provide all the energy the heart needs to beat and pump blood around the body.

‘In heart failure, it is thought that the heart begins to use more and more fatty acids for fuel and the mitochondria don’t use oxygen as efficiently. The heart begins to dilate, or get bigger, to compensate. At some point, as the heart becomes overloaded with fatty acids and lacks oxygen, specific protein molecules “uncouple” the mitochondria and no more energy is produced. These are called uncoupling proteins. The result is the heart is starved of both oxygen and the energy to pump, and it fails.‘But this is all theory; it hasn’t all been tested.

‘We’re looking at normal people as well as those with heart disease. For example, we have put people in a hypoxic (low oxygen) tank and looked at mountaineers going up Everest to understand the changes that occur when the heart is deprived of its normal amount of oxygen. We have also infused volunteers with fatty acids to see if that does lower the heart’s energetics.

‘You can also look at the effect of a high-fat diet – the hearts of normal people quickly look terrible on such a diet, while there is no effect in athletes at all. It shows that athlete’s bodies really are the norm and should be how we all look. It is our sedentary lifestyles that are wrong. We suffer without enough exercise.

‘Exercise turns out to be incredibly important for diabetics and older people. Our work has also helped lead to changes in cardiac surgery. In open-heart surgery, the heart is perfused with glucose-containing solutions so that the heart is not starved of fuel.

‘As well as working with healthy volunteers and patients, we also use animal models of obesity, diabetes, and heart failure to gain more understanding of the effects of diet and exercise on metabolism. This allows us to learn the pathway of chemical changes in heart cells that leads from increased fatty acids to the production of the uncoupling protein molecules.

‘We now know why betablocker drugs work, for example – they stop the effect of the uncoupling proteins. No one knew this before. By knowing the cellular mechanisms that lead to heart failure, we will be much more likely to come up with drugs to combat the disease.

‘We have also been able to show that lowering the amount of fatty acids in the diets of diabetic mice means they are less likely to have a heart attack and more likely to survive. We believe the same is probably true in humans.

‘After a heart attack, there is a dead area of the heart that has been deprived of oxygen. We have been looking at whether novel stem cell treatments could regenerate the dead heart tissue. We have done this in rats to understand whether it is safe and whether it might work.

‘So far, we have shown that adult stem cells from bone marrow are safe but don’t work. Some people have claimed to show that stem cells from the heart itself do differentiate and could provide all the types of heart cells you would need to repair damaged tissue. But I believe we need to understand a lot more about stem cells and their differentiation, and this is our current focus.

‘We have also invented a new food group, a food group beyond those of carbohydrates, proteins and fats that we have called ketone bodies. Ketone bodies are normally made in the liver from fat and are used to feed the brain in the absence of the glucose it would use otherwise (the brain can’t use fat for food).

‘We’ve developed a ketogenic diet that could help treat epilepsy, Alzheimer’s disease and Parkinson’s disease. It’s the worst diet – really unpleasant! It’s all fat and a bit of protein, and you can’t eat carbs. But the cognitive and physical performance of rodents is improved: they run up to 30% further on treadmills and their performance in maze tests is better. We have now gained permission to do a dosage study in humans.

‘As well as working with people with heart disease, diabetes and those who are obese, we do use animal models of these conditions. While the models of obesity are just fed high-fat diets, the models of type I and type II diabetes are bred commercially and we buy them in. Using MRI, during which the animals are anaesthetised, allows us to follow disease progression over time without having to kill so many animals to obtain tissues.

‘We do use surgery to make an infarct and give an animal model of heart disease. We then infuse stem cells through the tail vein to see if this can regenerate the tissue and provide the basis of a novel therapy.

‘The Biomedical Sciences Building offers better care of the animals, and is healthier for both animals and researchers. It is cleaner, handling the animals is easier, and the prevention of infections has been improved. It is just ideal.’