The multiple proarrhythmic roles of cardiac calcium-handling abnormalities: triggered activity, conduction abnormalities, beat-to-beat variability, and adverse remodelling

The Subcellular Distribution of Ryanodine Receptors and L-Type Ca2+ Channels Modulates Ca2+-Transient Properties and Spontaneous Ca2+-Release Events in Atrial Cardiomyocytes

“…Recent studies have identified a major role for cardiomyocyte Ca 2+ -handling abnormalities in cardiac arrhythmias and have provided insight into the underlying molecular mechanisms (Heijman et al, 2016a ; Landstrom et al, 2017 ). However, the impact of the subcellular distribution of RyR2 and LTCC on cardiomyocyte Ca 2+ -handling remains largely unknown.…”

“…Despite the significant advances in the treatment of cardiovascular diseases during the past 50 years, the frequency of cardiac arrhythmias, particularly atrial fibrillation (AF), is projected to increase, placing a significant burden on modern healthcare systems (Chugh et al, 2014 ; Roth et al, 2015 ; Morillo et al, 2017 ). Ca 2+ -handling abnormalities play a key role in ectopic activity and reentry, the two major arrhythmogenic mechanisms underlying AF (Heijman et al, 2014 , 2016a ; Landstrom et al, 2017 ). Dysfunctional ryanodine receptor type-2 (RyR2) channels, and/or SR Ca 2+ overload can promote the occurrence of spontaneous sarcoplasmic reticulum (SR) Ca 2+ -release events (SCaEs) (Heijman et al, 2016a ), which transiently increase the cytosolic Ca 2+ concentration, activating the Na + /Ca 2+ -exchanger type-1 (NCX1), resulting in a depolarizing transient-inward current and promoting delayed after depolarizations (DADs) and triggered activity.…”

“…Ca 2+ -handling abnormalities play a key role in ectopic activity and reentry, the two major arrhythmogenic mechanisms underlying AF (Heijman et al, 2014 , 2016a ; Landstrom et al, 2017 ). Dysfunctional ryanodine receptor type-2 (RyR2) channels, and/or SR Ca 2+ overload can promote the occurrence of spontaneous sarcoplasmic reticulum (SR) Ca 2+ -release events (SCaEs) (Heijman et al, 2016a ), which transiently increase the cytosolic Ca 2+ concentration, activating the Na + /Ca 2+ -exchanger type-1 (NCX1), resulting in a depolarizing transient-inward current and promoting delayed after depolarizations (DADs) and triggered activity. Although potential proarrhythmic effects of changes in RyR2 expression and phosphorylation have been extensively discussed (Dobrev and Wehrens, 2014 ; Houser, 2014 ), these studies have generally employed tissue homogenates, ignoring the subcellular structure of Ca 2+ -handling proteins.…”

Integrative computational modeling of calcium handling and cardiac arrhythmias

“…In addition to the calcium doors, heart muscle cells are also equipped with other doors responsible for the movements of other particles in and out of the cell, such as sodium, potassium, and chloride. Recently, scientists have found that calcium can regulate the activity of these other doors, making them easier or harder to open, highlighting the large responsibility of calcium in heart muscle cells (2). The role of calcium in heart muscle cells.…”

“…For several decades, scientists have been studying the role of calcium in heart muscle cells. They now know that in some heart diseases, such as fibrillation and heart failure, abnormalities in calcium regulation play a major role (2).…”