Protecting a broken heart: the discovery of remote ischemic preconditioning.

After a couple of weeks dominated by dialogue with moderate animal rights activists, and subsequently the response of the scientific community to threats by animal rights extremists,  it is refreshing to be able to turn again to an example of how research on rabbits and dogs is furthering medical progress.

The prospects of surviving a heart attack have improved greatly over the past few decades, and thanks  to the development of surgical techniques such as coronary artery bypass and clot-busting thrombolytic drugs many patients go on to live long and healthy lives who would previously have faced an early grave.  Despite this progress doctors and scientists are still looking for ways to further reduce the toll of death and infirmity that results from heart attacks; now a report on the BBC suggests that another important advance is in progress.

A team led by Professor Hans Botker of Aarhus University Hospital in Denmark reported a clinical trial of over 300 patients where a novel technique known as remote ischaemic preconditioning (rIPC) safely reduced the amount of damage suffered by the heart during ischemia, when its blood and oxygen supply is cut off during a heart attack (1).  rIPC is a phenomenon whereby short periods of ischemia in one tissue can protect a distant tissue or organ from longer periods of ischemia. In this trial the blood supply to muscles in the arm was cut off using a blood pressure cuff for brief periods in heart attack victims on their journey to hospital, and it was used in addition to established treatments.

So how does it work? Well the answer is that we still don’t know. Research in animals indicates that the tissue exposed to brief periods of ischemia release factors that then travel through the bloodstream to other organs where they alter the metabolism in that organ to make it more resistant to damage from oxygen starvation, but the identity of these factors had not yet been confirmed (2).  This raises an obvious question, if the mechanism is so poorly understood how was this phenomenon identified? After all without this knowledge  in vitro or computational studies could not have identified it, and doctors could hardly go around stopping the blood flow in the arms of heart attack victims without having a very good reason for doing so!

This story starts in the mid 1980’s when scientists studying heart attacks in dogs observed that while blocking a major coronary artery for an extended period resulted in the same damage seen in heart attacks in humans, brief blockage of blood flow did not result in this damage, even if repeated several times.  In fact they observed that the energy use in the heart was slower in later periods of transient ischemia than in the first period, reducing its need for oxygen, and postulated that multiple brief periods of ischemia in the heart might prevent it from damage in a subsequent longer period of ischemia. When they tested this in dogs they found that was indeed the case, four 5 minute periods of ischemia did indeed reduce the heart damage seen after a sustained 40 minute period of ischemia (3).  Subsequent experiments confirmed this finding, and in later clinical trials the technique was found to be beneficial for patients undergoing heart surgery where the supply of blood to the heart is cut off.  Despite this utility the technique of directly preconditioning the heart has been restricted to situations where it is possible to operate on the patient before the supply of blood to the heart muscle is cut off for a prolonged period, and it is not a viable option with heart attack victims.

At this point further analysis of the studies undertaken in dogs suggested a way to widen the clinical use of this technique, as it was noticed that preconditioning one area of heart tissue protected other areas from subsequent damage. Might it be possible to protect the heart by inducing transient ischemia in other tissues? Initial studies in animals and subsequent human trials examined transient ischemia of the mesentery and kidney, discovering that it could reduce damage to the heart. However inducing transient ischemia in the mesentery and kidney still required surgery and was hardly ideal for emergency situations. The breakthrough came with the demonstration by Yochai Birnbaum and colleagues at the Good Samaritan Hospital that inducing transient skeletal muscle ischemia in a rabbit model of heart attack substantially reduced the damage to the heart (4), a result subsequently confirmed by other scientists studying heart attack in rats and rabbits.  The significance of this discovery is that it is possible to block the blood flow to skeletal muscle through the use of a standard blood-pressure cuff, avoiding the necessity for additional surgery.

Thanks to pioneering work of Yochai Birnbaum and other animal researchers successful clinical trials of the blood pressure cuff to induce transient ischemia in limb muscles have been reported in children undergoing heart surgery (5) and now in heart attack victims.  We hope that in years to come this exciting new technique will fulfill its early promise and help save many lives.

Paul Browne, PhD

1)      Botker H. E. et al. “Remote ischemic conditioning before hospital admission, as a complement to angioplasty, and effect on myocardial salvage in patients with acute myocardial infarction: a randomized trail” The Lancet Volume 375 (9716), Pages 727-734 (2010) DOI:10.1016/S0140-6736(09)62001-8

2)      Shimizu M. et al. “Transient limb ischemia remotely preconditions through a humoral mechanism acting directly on the myocardium: evidence suggesting cross-species protection” Clinical Science, Volume 117, Pages 191-200 (2009) DOI:10.1042/CS20080523

3)       Murry C.E., Jennings R.B., Reimer K.A. “Preconditioning with ischemia: a delay of lethal cell injury in ischemic myocardium.” Circulation Vol.74(5), Pages 1124-1136 (1986) PMID: 3769170

4)      Birnbaum Y., Hale S.L. Kloner R.A. “Ischemic preconditioning at a distance: reduction of myocardial infarct size by partial reduction of blood supply combined with rapid stimulation of the gastrocnemius muscle in the rabbit.” Circulation Vol. 96(5), Pages 1641-1646 (1997) PMID: 9315559

5)      Cheung M.M. et al. Randomized controlled trial of the effects of remote ischemic preconditioning on children undergoing cardiac surgery: first application in humans” J. Am. Coll. Cardiol. Volume 47(11), Pages 2277-2282 (2006) doi:10.1016/j.jacc.2006.01.066