Modeling Pacemaker Deterioration with Age
December 4, 2017
Study models how sinoatrial node pacemaker activity changes in aged hearts
Heartbeat pacing is coordinated by a lump of specialized heart muscle tissue called the sinoatrial node (SAN), which integrates inputs from the brain with its own intrinsic pacemaking activity to meet the body’s metabolic demands. SAN function deteriorates in elderly people, in ways that are still not well understood. A paper published in The Journal of General Physiology by Technion-Israel Institute of Technology researchers Joachim Behar and Yael Yaniv shows how the use of mathematical modeling can provide insight about how SAN function deteriorates with age, and how it can be restored.
At its root, a SAN pacemaker cell beats spontaneously and generates electrical activity driven by current through plasma membrane channels and ion exchangers. An increase in the current into the cell triggers the next spontaneous electrical activity. Therefore, precise regulation of these plasma membrane components by internal pacemaker mechanisms is important to SAN pacemaking.
SAN pacemaking activity also involves internal signaling interactions, mainly Ca2+ and phosphate. Ca2+ ions are released from internal sources and activate channel and ion exchangers on the cell membrane. Ca2+ also regulates the mechanisms that control the level of phosphate in the cell, which is important since higher phosphate levels increase the activity of membrane channels and Ca2+ release from internal storage. Finally, signaling from the autonomic nervous system can modulate both plasma membrane and internal Ca2+ storage release pacemaking activity. Therefore, Ca2+ and phosphate determine the activity of membrane and internal components.
“By using a mathematical model, one can change one mechanism and see the others change in response. This provides a lot of insight into mechanisms that are hard or impossible to measure,” explains Yaniv, an assistant professor in the Technion Faculty of Biomedical Engineering.
To explore how SAN function deteriorates in aged cells, Behar and Yaniv based their model on an earlier one that takes into account both plasma membrane and SR pacemaker activity. That earlier model that describes the phonate activity, and incorporates nervous system inputs. In their new paper, they integrated into that model in vivo observations about how SAN function changes in aged mice.
Prior studies indicated that aged SAN cells have reduced current through the membrane channels and impaired release from the internal Ca2+ storage.
When Behar and Yaniv incorporated these factors into their new model, they observed that SAN pacemaker activity slowed down, just as it does in actual aged cells. The model also demonstrated how changes to these parameters affected the function of other SAN proteins: for example, by causing decreased currents from plasma membrane ion channels and from NCX in aged cells.
To find out how aged SAN cells’ internal clocks respond to inputs from the autonomic nervous system, the authors identified existing drugs that may help to restore function to an aged heart, so that it mimics a young one.
Earlier studies indicated that adult and aged mice have identical maximal heart rates in response to these drugs, but curiously, the simulated aged maximal pacemaker rate was slower than that of adults.
“When the model didn’t work we started looking at what else could be different about aged cells,” recalls Yaniv. The researchers wondered whether the mismatch could be the result of aged SAN pacemaker mechanisms having a change in the sensitivity to Ca2+ and phosphate. Indeed, adjusting the regulation of membranal and internal mechanisms by these parameters restored the maximal pacemaker rates of simulated aged cells.
The fact that the processes that drive SAN pacemaker function are so interconnected means it should be possible to target some components of the system to relieve functional deficits in others, even if the targeted protein is not the one malfunctioning. Leveraging this, the authors’ model predicts drug doses and genetic interventions that may help treat clinical SAN deterioration—something Behar and Yaniv plan to investigate next.
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