Coronary heart disease (CHD) is the end result of the accumulation of fatty deposits – plaques – within the walls of the arteries that supply the heart. The symptoms may go unnoticed for some time and over the course of decades these plaques, that at one time were merely streaks on the inside walls of arteries, become obstructions. If a large plaque ruptures, this can attract blood cells called platelets that within minutes form a clot in the artery, or the pieces of the plaque that have been dislodged may adhere elsewhere. Both events can reduce blood flow to areas of the heart muscle, leading to ischaemia – reduced oxygen supply – and it is the most common cause of a heart attack. Surprisingly, less than 70 per cent occlusion of an arterial vessel is not considered high risk for a heart attack. Nevertheless, the greater the occlusion, the more restricted the blood flow becomes to heart cells and this can result in areas of ischaemic activity on a semi-continuous basis. There is, however, a potential advantage to this otherwise life-threatening condition.

Researchers at the Bristol Heart Institute have found evidence that in some cases, heart cells have developed a ‘coping mechanism’ when the heart is subjected to erratic periods with low levels of oxygen. The cells appear to have developed the ability to shift their metabolic activity towards the anaerobic in order to manage the decreased oxygen level more effectively. This has been termed ‘ischaemic pre-conditioning’ and Chase believes that this increased hardiness of the cells may be the key to protecting the heart against reperfusion injury during coronary bypass surgery.

Heart cells have developed a 'coping mechanism'

During heart surgery the heart is deliberately stopped so that it is not beating while the surgeon operates. The blood, which would ordinarily have passed through the heart, passes instead through an external pump. During this process the heart undergoes a period of oxygen deprivation which can result in damage to the heart muscle. The problem is compounded when circulation is restored, since the sudden influx of oxygen and nutrients can cause inflammation and oxidative damage to the tissue. Rather than restoring normal function, the heart can be weakened even further. It appears, however, that in those patients with CHD, ischaemic pre-conditioning allows heart cells to maintain a level of activity that minimises the chances of being overwhelmed when normal blood flow is restored.

This state of pre-conditioning was discovered by Chase when attempting to develop a suitable model of coronary heart disease. Previous models have all been based on healthy rat models and therefore the effects seen when stopping and restarting these hearts does not accurately reflect those experienced by diseased hearts in situ. The question posed by Chase was therefore ‘Are diseased hearts different?’. The answer came from another type of rodent, the ‘apolipoprotein E knockout’ mouse, which has been genetically engineered to be the perfect model for atherosclerosis – the progressive narrowing and hardening of arteries. Providing it with a high-fat diet causes human-like atherosclerotic lesions and plaques.

Two sets of mice were fed for 24 weeks on either a high-fat or a normal diet. After the 24 weeks had elapsed, the coronary arteries and heart tissue of those on the high fat diet showed evidence of blocked coronary arteries and the heart muscle showed signs of infarction – death/loss of cellular structure.  Knowing these mice were suitable models for CHD, Chase excised their hearts and put them through a Langendorff heart preparation – a system designed to study coronary flow during cardiac activity. Both groups were exposed to 35 minutes of ischaemia followed by 45 minutes of reperfusion. The results were fascinating – the diseased hearts showed a 100 per cent recovery, whereas the normal hearts showed about 30 per cent recovery.

The diseased heart showed a 100 per cent recovery

But why was this the case? What is it about a diseased heart that gives it such strength under such strenuous conditions? Analysis of the diseased and healthy hearts revealed that metabolites such as adenosine triphosphate (ATP) and glycogen were reduced in the diseased heart, and lactate was at a higher level than that of a healthy one, giving rise to the pre-conditioned state that allows a CHD heart to cope better with ischaemic insults. Cellular damage was also noticeably different in diseased versus healthy hearts. When heart cell membranes become damaged, an enzyme called creatine kinase leaks out of the cells themselves. The extent of the damage can be determined by measuring the levels of this enzyme – the more creatine kinase you have, the more damage there is. Unsurprisingly, then, Chase found more creatine kinase in the normal hearts (low recovery) compared with diseased hearts (100 per cent recovery).

Protecting the heart from reperfusion injury is an ongoing field of research and Chase is hoping these new findings can help move the field on. As she explained: “Ischaemic and reperfusion injury occurs in any type of operation that requires a motionless, bloodless heart. So while this includes bypass surgery for coronary heart disease, it also includes valve replacements, arterial defect repair and aneurysm repair. In children too there are tons of congenital heart diseases, so although these diseases don't require bypass surgery as such, they can still suffer from ischaemic or reperfusion injury.”

Current cardio-protective techniques are largely based on preserving metabolites –  preserving ATP, preserving glycogen and reducing lactate formation. This always seemed like the obvious thing to do. However, what Chase’s research shows is that low levels of ATP and glycogen, and high levels of lactate, are actually beneficial and can help to protect the heart. From this point of view, it may be that the cardio-protective solutions we currently use are ineffective or inappropriate and require something of a rethink.

 

This work by Anabelle Chase, a postgraduate student at the Bristol Heart Institute, formed the basis of her PhD. It was funded by the British Heart Foundation. Anabelle won the first prize for best oral presentation at this year’s Joint Faculties’ Postgraduate Symposium.

Clinical Science at South Bristol