Spatial remodelling of calcium release units may impair cardiac electro-mechanical function: A simulation study

Area of Science:

• Cardiology
• Computational Biology
• Cellular Physiology

Background:

• Excitation-contraction coupling (E-C coupling) relies on close proximity between L-type Ca2+ channels (LCCs) and ryanodine receptors (RyRs) within calcium release units (CRUs).
• Remodeling of transverse tubules (TTs) in failing hearts can uncouple LCC-RyR structures, compromising E-C coupling and cardiac function.

Purpose of the Study:

• To investigate the relationship between LCC-RyR structural integrity and cardiac electro-mechanical function using a multiscale computational model.
• To explore how microstructural remodeling of CRUs affects calcium homeostasis and cardiomyocyte contractility in a failing heart.

Main Methods:

• Development of a multiscale mathematical model of a ventricular myocyte.
• Incorporation of a 2D subcellular Ca2+ reaction-diffusion sub-model, a cellular electrophysiology sub-model, and a cardiomyocyte contraction sub-model.
• Simulation of the effects of CRU microstructural remodeling on cardiac function.

Main Results:

• CRU microstructural remodeling disturbs Ca2+ homeostasis, leading to dyssynchronous Ca2+ transients.
• Structural remodeling delays the generation of isometric force in cardiomyocytes.
• The model demonstrates that altered CRU structure significantly impacts Ca2+ handling, cellular electrophysiology, and contractility.

Conclusions:

• Structural remodeling of CRUs is a key mechanism underlying the dysfunction of Ca2+ handling, cellular electrophysiology, and contractility in the failing heart.
• The study highlights the importance of LCC-RyR structural integrity for normal cardiac function.