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    By Byron Roberts | October 15th 2009 04:43 PM | Print | E-mail
    The human heart, a tireless organ that beats within our chests continuously for decades, continues to amaze me, in spite of my having studied it for several years now.  My continued amazement stems not from the fact that this muscle functions for so long, and for the most part without us being aware of it (although this is indeed phenomenal), but from the rich variety of behavior that it exhibits across multiple scales.  When I was first introduced to the heart, it was essentially as a ball of muscle divided into four chambers that were separated by valves.  Newly oxygenated blood arrived on the left side and was pushed out to the body, later returning to the right side before being pumped back out to the lungs.  Subsequent coursework revealed the basics of an electrical conduction system and pacemaker activity, as well as the existence of ion channels through which sodium, potassium and calcium flow in order to generate changes in voltage that ultimately lead to muscle contraction and relaxation.  I was also made aware of the basics of the cellular machinery that produces muscle contraction.  But it was not until I started my graduate work in cardiac electrophysiology that I really learned about the detailed machinery that exists within each and every muscle cell, the diversity of cell types that exist within the heart, and how subtle changes, either at the cellular level or in how individual cells are coupled together, can produce drastic changes in the behavior of the entire heart (some of them incompatible with life).

    If we zoom in to the level of a single cell, some pretty interesting behavior is already apparent.  If you measure the voltage across a muscle cell membrane as the cell is beating, the resulting trace is that of an action potential.  When a muscle cell is being stimulated at a particular frequency, the action potential for each resulting beat will last a particular amount of time, referred to as the action potential duration (APD).  Now, if you start to pace the cell faster and faster, you’ll see that the APD becomes shorter and shorter.  This is due to a property called APD restitution, and is especially important in the heart.  APD restitution simply means that the longer the time between beats (the diastolic interval), the longer the APD of the next beat will be.  APD restitution is important in the heart because, as we all know, the primary job of our heart is to pump blood.  If the heart starts to beat faster (as during exercise, for example), there still has to be enough time for the chambers to adequately fill before contracting to pump the blood out.  Without APD restitution, as the heart started to beat faster and faster, there would be less time available for the chambers to fill.  By shortening the APD at faster heart rates, restitution helps to ensure that enough time remains in between heartbeats for blood filling to occur (within a certain range, anyway).

    Another interesting phenomenon that is seen at the level of individual cells is known as action potential alternans, which is simply a condition in which long and short action potentials are alternating: a long beat is followed by a short one, followed by a long, and so on.  When a muscle cell is stimulated, calcium is released from intracellular storage known as the sarcoplasmic reticulum (SR), and the amount of calcium that is released from the SR is directly proportional to the amount of calcium that was stored in the SR to begin with (in other words, an SR that is very full will release a lot more calcium into the muscle cell’s cytoplasm than will an SR that is nearly depleted).  A larger calcium release event also translates to a longer action potential duration.  During the diastolic interval, miniature machines known as SERCA pumps move calcium from the cytoplasm back into the SR.  Action potential alternans arises when a heart is paced too quickly: if the diastolic interval is too short, there won’t be enough time for the SERCA pumps to sufficiently refill the SR.  This means that during the next beat, less calcium will be released from the SR, which will result in a shorter action potential.  A shorter action potential duration means that there will be more time available during the next diastolic interval for SERCA pumps to refill the SR.  This more-fully-stocked SR will then release more calcium during the next beat, resulting in a longer action potential.  The longer action potential leaves less time for SR filling during the next diastolic interval, and the cycle continues.  Action potential alternans is often easier to elicit in sick heart cells, but can be seen even in healthy hearts if they are paced fast enough.

    If we take a metaphorical step back from the level of a single cell to examine a region of hear tissue, we can see additional types of behavior among coupled cells that are not possible with isolated cells.  One very clinically important tissue-level phenomenon is known as reentry, which is a sort of short-circuiting that occurs in a region of the heart.  Rather than responding to cues from the heart’s normal pacemaker, electrical impulses in the reentry pathway continue to circle around, rapidly reactivating the affected region of heart muscle. If the affected region is large enough and/or the short circuit causes the heart to be fast enough, the heart can cease to be an effective pump altogether, possibly causing death..  The action potential alternans that I mentioned above, in addition to being an interesting phenomenon in of itself, is studied by many people because it can set the stage for reentry.

    I’ve tried to illustrate here just a couple of the many types of complex behavior that our hearts exhibit across multiple scales of time and space.  On the one hand, the heart is an elegant and, in some ways, simple machine.  However, there’s also a lot going on in each of the tens of millions of interconnected cells that make up a heart.  In general, it’s a good thing that we’re unaware of the complex orchestrations that must occur with each and every heartbeat.  That being said, take a moment from time to time to marvel at the complexity of even just this one part of our bodies that continues to keep us alive!