Multidimensional Role of Calcium in Atrial Fibrillation
The molecular changes in Ca-related signalling and related proteins offer a variety of opportunities to correct defective Ca handling (Figure 3). Several lead compounds targeting RyR2 diastolic Ca leak have been identified. The local anaesthetic tetracaine stabilizes RyR2 channels in their closed states, whereas the class IC antiarrhythmic drugs flecainide and propafenone have been reported to reduce RyR2 open probability by decreasing mean open time, an observation that has recently been disputed. Newer RyR2 inhibitors based on the structure of the β-blocker carvedilol prevent DAD-related arrhythmias by reducing mean RyR2 open time, thereby suppressing spontaneous SR Ca releases. Stabilization of the RyR2 channel complex is another potential approach. The 1,4-benzothiazepine derivative JTV519 (K201) attenuates AF inducibility in dogs, RyR2-induced SR Ca leak and arrhythmogenic activity in pulmonary vein cardiomyocytes, likely by increasing the affinity of FKBP12.6 for RyR2, and is a potential lead compound. Blockade of forward (Ca extrusion)-mode NCX with benzyloxyphenyl analogues such as KB-R7943, SEA0400, SN-6, and YM-244769 should suppress DADs/triggered activity, but with a risk of promoting Ca overload.
An alternative approach to target SR Ca leak is to reduce CaMKII activity. Proof of principle has been obtained in mouse AF models and small molecule inhibitors are under development. Local targeting of kinase or phosphatase function (e.g. targeting of inhibitor-1 of PP1) is another possible strategy: inhibition of I-1-mediated PP1-suppression normalizes RyR2 phosphorylation and prevents inducible ventricular arrhythmias. Finally, antioxidant molecules could prevent CaMKII activation by angiotensin-II/NADPH oxidase-related oxidant stress.
Although it is theoretically possible to prolong atrial RP by enhancing ICaL, there would be a risk of inducing ventricular EADs and acquired long-QT syndrome. IKCa is a potentially interesting target: small molecule inhibitors have shown AF suppressing properties in small animal models. Targeting specific ion channels activated by Ca-dependent arrhythmogenic remodelling is another possible strategy. Molecular motifs for IK1 block have been explored and provide opportunities for drug development.IKACh blockers are also under development and have efficacy for AF in ATR atria.
Another approach is to target Ca-dependent processes leading to arrhythmogenic remodelling, so-called 'upstream therapy'. ICaL down-regulation can be prevented by inhibiting steps in the signal transduction pathway, but the agents required are too toxic for in vivo use. Diminishing Ca loading with ICaL inhibitors is ineffective against remodelling induced by >24 h of ATR, but the T-type ICa (ICaT)-blocker mibefradil has shown efficacy. However, because of the non-specificity of mibefradil action, it is uncertain whether ICaT block is truly effective against ATR. MicroRNAs can be manipulated by adenoviral delivery of miRs or their antagonists (antagomirs), and chemical modifications like locked nucleotide chemistry increase stability and cell penetration. Tail vein injection of miR26 bearing adenovirus to mice on three consecutive days is able to boost cardiac miR26 expression and suppress AF in mice. Structural remodelling is another potential target. Ca-related processes that may lend themselves to therapeutic intervention include nuclear AT1R-dependent IP3R-related nuclear Ca signalling, fibroblast TRP channel Ca entry pathways and Ca-dependent calpain activation.
Novel Therapeutic Approaches Targeting Ca-related Components of Atrial Fibrillation Pathophysiology
Strategies for Prevention of Ca-related Focal Ectopy
The molecular changes in Ca-related signalling and related proteins offer a variety of opportunities to correct defective Ca handling (Figure 3). Several lead compounds targeting RyR2 diastolic Ca leak have been identified. The local anaesthetic tetracaine stabilizes RyR2 channels in their closed states, whereas the class IC antiarrhythmic drugs flecainide and propafenone have been reported to reduce RyR2 open probability by decreasing mean open time, an observation that has recently been disputed. Newer RyR2 inhibitors based on the structure of the β-blocker carvedilol prevent DAD-related arrhythmias by reducing mean RyR2 open time, thereby suppressing spontaneous SR Ca releases. Stabilization of the RyR2 channel complex is another potential approach. The 1,4-benzothiazepine derivative JTV519 (K201) attenuates AF inducibility in dogs, RyR2-induced SR Ca leak and arrhythmogenic activity in pulmonary vein cardiomyocytes, likely by increasing the affinity of FKBP12.6 for RyR2, and is a potential lead compound. Blockade of forward (Ca extrusion)-mode NCX with benzyloxyphenyl analogues such as KB-R7943, SEA0400, SN-6, and YM-244769 should suppress DADs/triggered activity, but with a risk of promoting Ca overload.
An alternative approach to target SR Ca leak is to reduce CaMKII activity. Proof of principle has been obtained in mouse AF models and small molecule inhibitors are under development. Local targeting of kinase or phosphatase function (e.g. targeting of inhibitor-1 of PP1) is another possible strategy: inhibition of I-1-mediated PP1-suppression normalizes RyR2 phosphorylation and prevents inducible ventricular arrhythmias. Finally, antioxidant molecules could prevent CaMKII activation by angiotensin-II/NADPH oxidase-related oxidant stress.
Targeting Atrial Fibrillation Due to Re-entry
Although it is theoretically possible to prolong atrial RP by enhancing ICaL, there would be a risk of inducing ventricular EADs and acquired long-QT syndrome. IKCa is a potentially interesting target: small molecule inhibitors have shown AF suppressing properties in small animal models. Targeting specific ion channels activated by Ca-dependent arrhythmogenic remodelling is another possible strategy. Molecular motifs for IK1 block have been explored and provide opportunities for drug development.IKACh blockers are also under development and have efficacy for AF in ATR atria.
Another approach is to target Ca-dependent processes leading to arrhythmogenic remodelling, so-called 'upstream therapy'. ICaL down-regulation can be prevented by inhibiting steps in the signal transduction pathway, but the agents required are too toxic for in vivo use. Diminishing Ca loading with ICaL inhibitors is ineffective against remodelling induced by >24 h of ATR, but the T-type ICa (ICaT)-blocker mibefradil has shown efficacy. However, because of the non-specificity of mibefradil action, it is uncertain whether ICaT block is truly effective against ATR. MicroRNAs can be manipulated by adenoviral delivery of miRs or their antagonists (antagomirs), and chemical modifications like locked nucleotide chemistry increase stability and cell penetration. Tail vein injection of miR26 bearing adenovirus to mice on three consecutive days is able to boost cardiac miR26 expression and suppress AF in mice. Structural remodelling is another potential target. Ca-related processes that may lend themselves to therapeutic intervention include nuclear AT1R-dependent IP3R-related nuclear Ca signalling, fibroblast TRP channel Ca entry pathways and Ca-dependent calpain activation.
SHARE
