New antiarrhythmic targets to control intracellular calcium handling

Abstract

Sudden cardiac death due to ventricular arrhythmias is a major problem. Drug therapies to prevent SCD do not provide satisfying results, leading to the demand for new antiarrhythmic strategies. New targets include Ca(2+)/Calmodulin-dependent protein kinase II (CaMKII), the Na/Ca exchanger (NCX), the Ryanodine receptor (RyR, and its associated protein FKBP12.6 (Calstabin)) and the late component of the sodium current (I Na-Late ), all related to intracellular calcium (Ca(2+)) handling. In this review, drugs interfering with these targets (SEA-0400, K201, KN-93, W7, ranolazine, sophocarpine, and GS-967) are evaluated and their future as clinical compounds is considered. These new targets prove to be interesting; however more insight into long-term drug effects is necessary before clinical applicability becomes reality.

Fig. 1

Action potential and ion currents. Phases of the action potential and the responsible ion currents are discussed in the text

Fig. 2

Calcium handling. 0; Sodium enters the cell, creating the AP upstroke. 1; Calcium enters via the LTCC facilitating the plateau phase of the AP and initiating CICR. 2; via RyR on the sarcoplasmic reticulum leading to 3; calcium binding to the contractile elements: excitation-contraction coupling. 4; NCX transports calcium from the cell in exchange for sodium. 5; calcium is pumped back into the SR via SERCA, together with 4 this leads to relaxation of the contractile elements and the end of the plateau phase. 6; Potassium restores the negative membrane potential

Fig. 3

a EAD and DAD formation. SR calcium overload leads to increased [Ca²⁺]_i. This can lead to prolonged action potential duration creating a calcium window current potentially leading to EAD (3). Increased [Ca²⁺]_i on the other hand can lead to spontaneous calcium release via CICR resulting in either EADs (4) or DADs (2) via NCX. Also, late I _na is able to increase [Ca]_i via NCX_r, hereby contributing to EAD formation. Numbers corresponding to black numbers in b. b 1; normal action potential and I _CaL and I _NCX. 2; DAD occurring due to forward NCX activity (*). 3; EAD due to calcium window current via LTCC (**). 4; EAD due to forward NCX activity (***)

Fig. 4

a RyR open probability, [Ca²⁺]_SR, and sparks. Calcium sparks occur when [Ca²⁺]_SR reaches RyR opening threshold. RyR opening threshold is influenced by the open probability of RyR. Higher open probability lowers the threshold. [Ca²⁺]_SR is affected by total [Ca²⁺]_in and SERCA. b In heart failure [Ca²⁺]_SR is lowered but the RyR open threshold is lowered more extensively rendering [Ca²⁺]_SR higher then threshold

Fig. 5

Schematic overview of experimental approaches that have been performed to test efficacy and antiarrhythmic potency of drugs targeting NCX, RyR, CamKII and late I_Na. References are stated behind the model. S stands for suppressive, P stands for preventive. Asterisk indicates papers in which no plasma concentration was measured. Dagger indicates model in which proarrhythmic events were observed