Mechanism underlying impaired cardiac pacemaking rhythm during ischemia: A simulation study

Area of Science:

• Cardiovascular Physiology
• Computational Biology
• Cardiac Electrophysiology

Background:

• Ischemia significantly impacts cardiac pacemaker function, specifically the sinoatrial node (SAN).
• The precise ionic mechanisms driving ischemia-induced SAN dysfunction are not fully understood.
• Understanding these mechanisms is crucial for treating bradycardia and conduction abnormalities.

Purpose of the Study:

• To investigate the ionic underpinnings of sinoatrial node (SAN) dysfunction caused by cardiac ischemia.
• To model the effects of ischemia on SAN electrical activity and conduction using computational approaches.
• To explore the influence of vagal tone on pacemaker function in both normal and ischemic conditions.

Main Methods:

• Developed multi-scale computational models of rabbit SAN and atrial cells, incorporating experimental data on ischemia-induced ion channel and homeostasis changes.
• Integrated cell models into an anatomically detailed 2D SAN-atrium model.
• Simulated cardiac action potentials, pacemaking rates, conduction velocities, and the effects of vagal stimulation.

Main Results:

• Ischemia significantly slowed SAN pacemaking rate at the cellular level, primarily due to altered Na⁺-Ca²⁺ exchange and ATP-sensitive potassium currents.
• In a 2D model, ischemia reduced both SAN pacemaking rate and action potential conduction velocity into atrial tissue.
• Simulated vagal activity exacerbated ischemia's effects, leading to potential SAN arrest and conduction block, characteristic of sick sinus syndrome.

Conclusions:

• This study elucidates key ionic mechanisms contributing to ischemia-induced SAN dysfunction, including bradycardia and conduction block.
• Identified specific ion conductances as critical factors in the development of these arrhythmias.
• Provides novel insights into the pathophysiology of sick sinus syndrome under ischemic conditions.