From ionic to cellular variability in human atrial myocytes: an integrative computational and experimental study

Area of Science:

• Cardiovascular Physiology
• Computational Biology
• Biophysics

Background:

• Individual variability in human cardiomyocyte function influences disease susceptibility and treatment response.
• Experimental studies on human cardiomyocytes face challenges due to high variability and limited tissue availability.
• Computational models offer a valuable tool to complement experimental investigations.

Purpose of the Study:

• To investigate the impact of action potential (AP) and subcellular ionic density variability on calcium (Ca2+) transient dynamics in human cardiomyocytes.
• To integrate computational modeling with experimental data from human atrial myocytes.
• To understand the sources and consequences of electrophysiological variability in the human atrium.

Main Methods:

• Computational modeling of human cardiomyocytes using patient-specific data.
• Experimental recordings from human atrial appendage cardiomyocytes.
• Calibration of computational models using experimental AP and ion channel recordings.
• Analysis of variability in ionic conductances and Ca2+ transient dynamics.

Main Results:

• Significant variability in APs and ionic densities was observed, even within a homogenous patient cohort, leading to large variations in ionic conductances.
• Experimentally calibrated models reproduced experimental APs, even when the generic model's AP characteristics differed.
• Model calibration with AP recordings restricted variability in upstroke and resting potential ionic densities, but repolarization currents allowed for substantial variability.
• Constrained model populations exhibited three distinct Ca2+ transient phenotypes, differing in intracellular Ca2+ handling and Na+/Ca2+ extrusion.

Conclusions:

• Variability in human atrial electrophysiology is substantial and impacts Ca2+ handling.
• Computational models integrated with experimental data provide insights into cellular variability.
• Reduced Na+/Ca2+ exchanger activity is a key mechanism for diastolic Ca2+ fluctuations in human atrial myocytes.