Monthly Archives: March 2010

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.

Figure A is an overview of a heart and coronary artery showing damage (dead heart muscle) caused by a heart attack. Figure B is a cross-section of the coronary artery with plaque buildup and a blood clot. Image displayed courtesy of the National Heart, Lung and Blood Institute.

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

A Curious Tale: Researchers and their Animals

Below is an account of how one researcher (Scicurious from the Neurotopia blog) views her animals, and the lengths she goes to ensure their welfare. Although such relationships vary from researcher to researcher, this account is almost certainly one which many researchers and animal care technicians will sympathise with. Scicurious (blogging pseudonym) is currently a grad student working towards a PhD in Physiology. This piece was originally posted as a post within a post on Neurotopia, and has been reprinted with full permission from the author.

Every day, at the lab, I head up to the animal colony. It’s my responsibility, and even though it’s work that, as a grad student, I probably shouldn’t be doing (I should be concentrating on other stuff and leaving this to the techs), I enjoy it. I have to sacrifice animals in my line of work, and taking care of the breeding colony, bringing new animals into the world, helps me feel a little bit better about it.

It’s more than kindness that makes me want to treat them well. Sick, uncared-for animals do not produce good data. It pays to have an animal caretaker that works well with their animals, as scared animals also do not produce good data. They benefit, and I benefit.

And the world benefits. Many people do not understand the value of animal research in neuroscience, the important things that can be learned from animals and applied to humans. Animal tests for anxiety, depression, addiction, or OCD may not be perfectly analogous, but they can tell you a great deal about how these diseases work. We can develop new treatments and cures. Progress is slow, but it’s essential. Once you have seen some of the people suffering with anxiety, depression, or addiction, looking entirely normal and yet completely unable to live their lives, you cannot just turn away. You want to help. These issues are not just problems of willpower, or problems of just needing to cheer up or relax. These problems originate in the brain, and in order to come to an understanding and a cure, we need to do research. And research into neurotransmitters, protein and gene expression levels, transporters, and signaling from one area to another is something that can still only be done in animals.

I work with animals. I am there for them rain or shine. I hike in to work to care for them when the roads are impassable with snow. I race in to work to make sure they have heat or cooling when the power goes out. During one paradigm, I did not get a day off for almost six months, because I had to care for them every day and no one else could replace me. Some people have it worse. I have heard heroic stories of vet techs remaining during a mandatory hurricane evacuation, stringing battery powered Christmas lights up in the rooms, and feeding and watering the animals every day, sometimes with water they had to beg from the Red Cross. I have heard stories of students, post-docs, and techs staying up all night to care for a sick or injured animal, working insane hours to preserve something as small as a mouse. And I have seen some of these same people near tears when an animal is put down. Even when the animal is put down for research reasons, it doesn’t stop us from caring.

I work with animals and I care for them a lot. As far as they can, they care for me as well. They don’t bite unless they have good reason. They cuddle in my arms, snuffling into my armpits where it’s warm. When they have injuries, they let me help them to the extent that I can. The species I work with doesn’t have a reputation for being very friendly, but we work well together.

Birth and death, I am there at every single moment in the life of my animals. I help sometimes to bring them into the world. I help to raise them, especially if their parents cannot do it very well (due to genetic issues or temperament). I feed them, I clean their living spaces. When they are young, I play with them. When they are adults, I do my experiments, treating them as gently as possible, and never forgetting that they are living beings worthy of respect and care. When they are older, I care for them, and make their lives easier. And when it’s time for them to go, I am there for them, too, to make it as painless and quick as possible. Can everyone say the same of their pet hamster or the burger they ate?

Many of the students, techs, and PIs that I work with have expressed similar feelings toward the animals they use. We respect them for what they can teach us, and we treat them well. But other people do not understand. And sometimes, they may understand, and they don’t agree. And that’s ok. I took my qualifying exams while people protested outside my building. But there’s disagreement, and then there’s…something else.

The other day I got something like this in my inbox:

“I hope what you do to animals is inflicted on your children”.

Just looking at that sentence makes my heart rate speed up, and my mind almost reels. I couldn’t get it out of my head. For several nights after that I dreamed that people were threatening me, entering my house, hurting my pets. The last dream I had involved an activist holding a gun to my head. Nights like those you don’t get a lot of sleep. I started checking my locks three times or more.

And this is nothing compared to what the bigger fish at my MRU get. I have heard of death threats, threats involving their children and noting where they go to school. At other institutions, people’s cars get burned, their houses get torched or flooded (or something their neighbors do by mistake), and fake or real bombs are dropped on their doorsteps. We are scared to communicate what we do to anyone outside of science. People ask and I say I’m a chemist. We fear the hatred and the accusations.

We are not monsters. We are the people trying to find the cures. Most people who go into biomedical science do it partly out of interest and partly out of a sense of duty. We see problems and we want to solve them. We want to help people. Many of us go into certain disciplines due to personal experience (could be very personal, friends, or family) with the problems involved: alcoholism, diabetes, cystic fibrosis, depression.

We are trying to help. That makes these threats hurt even more. The very people we are trying to help sometimes hate us for what we are doing. Sometimes, this makes us angry and cynical. Right now, it just makes me sad. And always, it makes us afraid. These people could destroy our lives, and the lives of our families, they could destroy our work, and they could hurt our animals.

And this is why its so important to speak out about our research. We need to tell people what we do and why we do it. We need to make it something that is understood, not feared, and understood to be necessary. The more the public knows and understands what we do and why we do it, the more they will help us. They will see the threats that some people are making as the actions of those too blinded by their views to keep to an open, legal protest. If we can get the public on our side, we may not feel like we have to hide our professions. We may feel that we can work without fear. ‘Til then, I’ll keep getting emails. And keep having nightmares. And keep on going. My work, and the animals I care for, are more important than fear.

Scicurious

Neurotopia Blog