Abstract
The role of Na+ homeostasis in cardiac pacemaking is not well established. Blocking of the Na+-K+ ATPase (NKA) to raise intracellular Na+ concentration ([Na+]i) in ventricles, thereby reducing Ca2+ removal by the Na+-Ca2+ exchanger (NCX), is widely used to improve cardiac inotropy in patients with congestive heart failure. However, NKA-blocking agents have a narrow therapeutic window, and cardiotoxic effects are common, as excessive Ca2+ accumulation is pro-arrhythmic and decreases lusitropy. Here, we updated an existing mathematical model of the mouse sinoatrial node (SAN) myocyte to determine the effects of increasing [Na+]i on pacemaker cell function, and test whether high [Na+]i levels have disrupting effects similar to those of cardiac glycosides in the ventricle. Model parameter sensitivity analysis revealed that NKA modulation impacts Na+ and Ca2+ homeostasis, as well as several action potential (AP) characteristics. NKA dynamically modulates cell automaticity: upon NKA inhibition SAN firing rate instantaneously increases, due to direct effects on membrane potential (Em) dynamics, and slowly continues to increase over time, while Na+ and Ca2+ accumulate. Simulations of various degrees of block showed that Na+ overload can even stop SAN firing. Thus [Na+]i plays a fundamental role in the regulation of pacemaker activity.
| Original language | English (US) |
|---|---|
| Title of host publication | Computing in Cardiology Conference, CinC 2016 |
| Publisher | IEEE Computer Society |
| Pages | 765-768 |
| Number of pages | 4 |
| Volume | 43 |
| ISBN (Electronic) | 9781509008964 |
| State | Published - Mar 1 2016 |
| Event | 43rd Computing in Cardiology Conference, CinC 2016 - Vancouver, Canada Duration: Sep 11 2016 → Sep 14 2016 |
Other
| Other | 43rd Computing in Cardiology Conference, CinC 2016 |
|---|---|
| Country | Canada |
| City | Vancouver |
| Period | 9/11/16 → 9/14/16 |
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ASJC Scopus subject areas
- Computer Science(all)
- Cardiology and Cardiovascular Medicine
Cite this
Dynamic regulation of pacemaker activity by the Na+-K+ pump. / Morotti, Stefano; Clair, Joshua R.St; Proenza, Catherine; Grandi, Eleonora.
Computing in Cardiology Conference, CinC 2016. Vol. 43 IEEE Computer Society, 2016. p. 765-768 7868855.Research output: Chapter in Book/Report/Conference proceeding › Conference contribution
}
TY - GEN
T1 - Dynamic regulation of pacemaker activity by the Na+-K+ pump
AU - Morotti, Stefano
AU - Clair, Joshua R.St
AU - Proenza, Catherine
AU - Grandi, Eleonora
PY - 2016/3/1
Y1 - 2016/3/1
N2 - The role of Na+ homeostasis in cardiac pacemaking is not well established. Blocking of the Na+-K+ ATPase (NKA) to raise intracellular Na+ concentration ([Na+]i) in ventricles, thereby reducing Ca2+ removal by the Na+-Ca2+ exchanger (NCX), is widely used to improve cardiac inotropy in patients with congestive heart failure. However, NKA-blocking agents have a narrow therapeutic window, and cardiotoxic effects are common, as excessive Ca2+ accumulation is pro-arrhythmic and decreases lusitropy. Here, we updated an existing mathematical model of the mouse sinoatrial node (SAN) myocyte to determine the effects of increasing [Na+]i on pacemaker cell function, and test whether high [Na+]i levels have disrupting effects similar to those of cardiac glycosides in the ventricle. Model parameter sensitivity analysis revealed that NKA modulation impacts Na+ and Ca2+ homeostasis, as well as several action potential (AP) characteristics. NKA dynamically modulates cell automaticity: upon NKA inhibition SAN firing rate instantaneously increases, due to direct effects on membrane potential (Em) dynamics, and slowly continues to increase over time, while Na+ and Ca2+ accumulate. Simulations of various degrees of block showed that Na+ overload can even stop SAN firing. Thus [Na+]i plays a fundamental role in the regulation of pacemaker activity.
AB - The role of Na+ homeostasis in cardiac pacemaking is not well established. Blocking of the Na+-K+ ATPase (NKA) to raise intracellular Na+ concentration ([Na+]i) in ventricles, thereby reducing Ca2+ removal by the Na+-Ca2+ exchanger (NCX), is widely used to improve cardiac inotropy in patients with congestive heart failure. However, NKA-blocking agents have a narrow therapeutic window, and cardiotoxic effects are common, as excessive Ca2+ accumulation is pro-arrhythmic and decreases lusitropy. Here, we updated an existing mathematical model of the mouse sinoatrial node (SAN) myocyte to determine the effects of increasing [Na+]i on pacemaker cell function, and test whether high [Na+]i levels have disrupting effects similar to those of cardiac glycosides in the ventricle. Model parameter sensitivity analysis revealed that NKA modulation impacts Na+ and Ca2+ homeostasis, as well as several action potential (AP) characteristics. NKA dynamically modulates cell automaticity: upon NKA inhibition SAN firing rate instantaneously increases, due to direct effects on membrane potential (Em) dynamics, and slowly continues to increase over time, while Na+ and Ca2+ accumulate. Simulations of various degrees of block showed that Na+ overload can even stop SAN firing. Thus [Na+]i plays a fundamental role in the regulation of pacemaker activity.
UR - http://www.scopus.com/inward/record.url?scp=85016130339&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85016130339&partnerID=8YFLogxK
M3 - Conference contribution
AN - SCOPUS:85016130339
VL - 43
SP - 765
EP - 768
BT - Computing in Cardiology Conference, CinC 2016
PB - IEEE Computer Society
ER -