Ionic mechanisms underlying human atrial action potential properties: insights from a mathematical model

TLDR

The mechanisms underlying many key properties of the human atrial action potential remain poorly understood. We constructed a mathematical model of the atrial action potential using human atrial myocyte data to parameterize K⁺, Na⁺, and Ca²⁺ currents, along with pump, exchanger, and background currents. The model reproduces experimentally recorded atrial action potentials, accurately mimics responses to rate changes, L‑type Ca²⁺ channel blockade, Na⁺/Ca²⁺ exchanger inhibition, and transient outward current variations, and explains rate‑dependent action potential duration adaptation and morphological variability through incomplete L‑type Ca²⁺ recovery and delayed rectifier deactivation, thereby offering mechanistic insight into clinically relevant atrial electrophysiology.

Abstract

The mechanisms underlying many important properties of the human atrial action potential (AP) are poorly understood. Using specific formulations of the K + , Na + , and Ca 2+ currents based on data recorded from human atrial myocytes, along with representations of pump, exchange, and background currents, we developed a mathematical model of the AP. The model AP resembles APs recorded from human atrial samples and responds to rate changes, L-type Ca 2+ current blockade, Na + /Ca 2+ exchanger inhibition, and variations in transient outward current amplitude in a fashion similar to experimental recordings. Rate-dependent adaptation of AP duration, an important determinant of susceptibility to atrial fibrillation, was attributable to incomplete L-type Ca 2+ current recovery from inactivation and incomplete delayed rectifier current deactivation at rapid rates. Experimental observations of variable AP morphology could be accounted for by changes in transient outward current density, as suggested experimentally. We conclude that this mathematical model of the human atrial AP reproduces a variety of observed AP behaviors and provides insights into the mechanisms of clinically important AP properties.