Arrhythmogenic late Ca ²⁺ sparks in failing heart cells and their control by action potential configuration

Abstract

Sudden death in heart failure patients is a major clinical problem worldwide, but it is unclear how arrhythmogenic early afterdepolarizations (EADs) are triggered in failing heart cells. To examine EAD initiation, high-sensitivity intracellular Ca2+ measurements were combined with action potential voltage clamp techniques in a physiologically relevant heart failure model. In failing cells, the loss of Ca2+ release synchrony at the start of the action potential leads to an increase in number of microscopic intracellular Ca2+ release events (“late” Ca2+ sparks) during phase 2–3 of the action potential. These late Ca2+ sparks prolong the Ca2+ transient that activates contraction and can trigger propagating microscopic Ca2+ ripples, larger macroscopic Ca2+ waves, and EADs. Modification of the action potential to include steps to different potentials revealed the amount of current generated by these late Ca2+ sparks and their (subsequent) spatiotemporal summation into Ca2+ ripples/waves. Comparison of this current to the net current that causes action potential repolarization shows that late Ca2+ sparks provide a mechanism for EAD initiation. Computer simulations confirmed that this forms the basis of a strong oscillatory positive feedback system that can act in parallel with other purely voltage-dependent ionic mechanisms for EAD initiation. In failing heart cells, restoration of the action potential to a nonfailing phase 1 configuration improved the synchrony of excitation–contraction coupling, increased Ca2+ transient amplitude, and suppressed late Ca2+ sparks. Therapeutic control of late Ca2+ spark activity may provide an additional approach for treating heart failure and reduce the risk for sudden cardiac death.

Inducing Ito,f and phase 1 repolarization of the cardiac action potential with a Kv4.3/KChIP2.1 bicistronic transgene

“…Such results support the idea that modulation of I to,f could be beneficial in heart failure [4]. We recently showed that electrophysiological restoration of phase 1 of the AP can improve SR release synchrony, suppress arrhythmogenic late Ca 2+ spark production and increase the amplitude of the Ca 2+ transient in a heart failure model [16] in agreement with the earlier demonstration that the loss of human phase 1 repolarization impairs excitation-contraction coupling (ECC) [14]. However, increasing I to,f pharmacologically (with the I to agonist NS5806) in a dog ventricular wedge preparation led to the emergence of Brugada-like electrical abnormalities [17] while in intact rabbit heart, NS5806 also promoted arrhythmias (although Brugada-like behaviour did not necessarily appear) and was suggested to be the consequence of defective Ca 2+ cycling [18].…”

“…Computer simulations have also shown an abrupt reduction in AP duration at ~0.13 nS/pF (corresponding to ~14 pA/pF) [ 57 ] in agreement with our results. While such an AP collapse might recapitulate Brugada syndrome [ 17 ], our data shows that controlled Kv4.3/KChIP2.1 expression and restoration of I to,f could be beneficial in reducing AP triangulation and beat-to-beat variability (the latter probably reflecting a more synchronous Ca 2+ release [ 16 , 58 ]). That modulating these key components of I to,f might reduce the risk of arrhythmia is also supported by the observation that increasing KChIP2 expression (or inhibiting miR-34) under pathologic conditions prevented reentry arrhythmias [ 46 ].…”

PDE5 Inhibition Suppresses Ventricular Arrhythmias by Reducing SR Ca 2+ Content

“…In view of the role of Ca 2+ in the generation of DADs, 4 – 6 , 21 , 35 subsequent experiments were designed to determine whether the antiarrhythmic effects of sildenafil were mediated by changes in intracellular Ca 2+ cycling. Cellular calcium waves were induced in voltage-clamped left ventricular myocytes by raising the external Ca 2+ concentration to 10 to 15 mmol/L to increase SR Ca 2+ content (control, 44.3±12.6 µmol/L; high Ca 2+ , 104.4±14.6 µmol/L; P =0.004; Figure IV in the Data Supplement ).…”

Cardiomyocyte Na+ and Ca2+ mishandling drives vicious cycle involving CaMKII, ROS, and ryanodine receptors

“…2). The effects of dantrolene on APD (and EAD formation) might be explained by the attenuation of SR Ca 2+ leak-induced CaMKII activity, changes in myocyte Na + and Ca 2+ loading, enhanced inward NCX, and late Ca 2+ sparks, which can activate the vicious cycle and influence AP configuration [14]. Dantrolene also markedly attenuated APD prolongation, alternans, and spontaneous diastolic activities (i.e., DADs, sAPs) in hiPSC-CMs carrying SCN5A N406K mutation, highlighting the critical role of SR Ca 2+ leak (and the activated vicious cycle) in these arrhythmias (Fig.…”