February has been designated Heart Month by the American Heart Association, the CDC, and several other organizations concerned with heart disease and ailments. The goal of Heart Month is to raise awareness of heart diseases and steps individuals can take to prevent them. It is also a good time for the Biophysical Society to highlight how advances in basic research contribute to our understanding of these diseases. BPS member David Eisner, the BHF Professor of Cardiac Physiology at the University of Manchester in the United Kingdom has taken the time to share his lab’s research on heart functioning with us.
We study calcium signaling in the heart and, specifically, what controls the intracellular concentration of calcium ([Ca2+]i ). Each heartbeat is initiated by a rise of [Ca2+]i; the greater the rise, the stronger the heart beats. During exercise, the stronger contraction of the heart results from an increase in the size of the rise of [Ca2+]i. As well as studying the normal regulation of [Ca2+]i, we are also interested in what happens in disease situations such as heart failure and cardiac arrhythmias. One of the reasons that the hearts beats more weakly in heart failure is because the rise of [Ca2+]i is smaller than in healthy conditions. The mechanisms responsible for this are still being unraveled. Many cardiac arrhythmias result from abnormalities of calcium signaling, in particular involving a rise of [Ca2+]i which occurs at the wrong part of the cardiac cycle. Again, our research aims to understand the origins of these changes.
Why is your research important to those concerned about these diseases?
Understanding cardiac disease requires a much better understanding of the basic physiology of the heart. The fundamental unit of the heart is the cardiac muscle cell (myocyte) and it is at this level that most of our work is focused. We use patch clamp to measure the movements of calcium across the membranes surrounding these cells and combine this with the use of fluorescent indicators to measure changes of [Ca2+]i. As well as providing information about the normal working of the heart, these sort of studies will reveal the changes in disease. Furthermore, cellular studies are essential for developing therapies against these conditions. In this context it is important to note that, although enormous progress has been made, the progonosis for someone diagnosed with heart failure is still bleak.
How did you get into this area of research?
When I was at school I wanted to study physics and had never heard of physiology. At university I was taught physiology as the application of physics to the body. Following undergraduate studies, I did my PhD with Denis Noble in Oxford where I worked with Jon Lederer (now at the University of Maryland) studying the control of contraction in the heart. I can still remember the sense of immediate gratification when one pushed a sharp microelectrode into a piece of cardiac muscle and heard the change of pitch of the audio amplifier. At that time it was impossible to do electrophysiological recordings on single cells and methods were not available to measure intracellular calcium. However advances in these areas meant that it became possible to study calcium signaling in the heart.
How long have you been working on it?
Since the early 1980s! My own research interests began very much at the basic science end of the subject but, over time, together with my long term collaborator Andrew Trafford, we have investigated disease models.
Do you receive public funding for this work? If So, from what agency?
Most of my funding comes from the British Heart Foundation (BHF). This is a charity supported by the general public. It is chastening to know that our research is supported by countless volunteers. The funding environment in the UK is very different from that in the US with a much smaller fraction of research supported by government funds.
Have you had any surprise findings thus far?
We obtained one very surprising result when we did experiments to increase the opening of the sarcoplasmic reticulum (SR) release channel (the ryanodine receptor, RyR). We had confidently expected that this would increase the size of the Ca signal and contraction. However, we found that the calcium signal was only increased for a couple of couple of beats before returning to normal levels. The explanation of this result turned out to be that the increased release of calcium from the SR decreased SR Ca content. This was the first hint we had of what has turned out to be a much more general phenomenon; the interaction between the various Ca handling pathways results in complicated, emergent behavior which is difficult to predict in advance. At the simplest level, these results arise from the fact that the cardiac cell is in calcium flux balance. On each beat the amount of calcium that enters the cell must exactly balance that which leaves. This highlights the need to study calcium signaling in an integrated way.
What is particularly interesting about the work from the perspective of other researchers?
As a result of our work, others now appreciate that, on each beat, the cell is in calcium flux balance. This point has to be borne in mind when trying to explain changes in cardiac contractility.
What is particularly interesting about the work from the perspective of the public?
The general public always seem fascinated when they are shown electrical and calcium signals from cardiac cells. They are amazed by the fact that the heart beats repetitively even when outside the body. It is a privilege to lecture to the public. I always think that it is a pity that most people know much more about outer space than about their own bodies.
Do you have a cool image you want to share with the blog post related to this research?
The image at the top of this blog post (work by Jessica Caldwell, Andrew Trafford and colleagues) shows ventricular cells connected together. The horizontal bands are the transverse tubules which invaginate the cell. We are currently studying the cellular mechanisms that ensure that the transverse tubule network is laid down in this precise arrangement and why it disappears in heart failure.