Flecainide: Current status and perspectives in arrhythmia management

Andrikopoulos, George; Pastromas, Sokratis; Tzeis, Stylianos

doi:10.4330/wjc.v7.i2.76

Cited by 76 publications

(77 citation statements)

References 58 publications

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“… 44 These compounds are sorted in Table 1 according to their IC 50 values. In addition, we included three known drugs – ranolazine, 45 lidocaine, 46 and flecainide 47 – that are known to block hNa v 1.5 in our validation set. All of the ligands were prepared using the LigPrep module in the Schrodinger drug discovery suite, followed by ensemble-based docking against dominant hNa v 1.5 conformations obtained from RMSD clustering.…”

Section: Methods and Computational Detailsmentioning

confidence: 99%

Modeling the human Na<sub>v</sub>1.5 sodium channel: structural and mechanistic insights of ion permeation and drug blockade

Ahmed

Hasani

Houghton³

et al. 2017

DDDT

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Abnormalities in the human Nav1.5 (hNav1.5) voltage-gated sodium ion channel (VGSC) are associated with a wide range of cardiac problems and diseases in humans. Current structural models of hNav1.5 are still far from complete and, consequently, their ability to study atomistic interactions of this channel is very limited. Here, we report a comprehensive atomistic model of the hNav1.5 ion channel, constructed using homology modeling technique and refined through long molecular dynamics simulations (680 ns) in the lipid membrane bilayer. Our model was comprehensively validated by using reported mutagenesis data, comparisons with previous models, and binding to a panel of known hNav1.5 blockers. The relatively long classical MD simulation was sufficient to observe a natural sodium permeation event across the channel’s selectivity filters to reach the channel’s central cavity, together with the identification of a unique role of the lysine residue. Electrostatic potential calculations revealed the existence of two potential binding sites for the sodium ion at the outer selectivity filters. To obtain further mechanistic insight into the permeation event from the central cavity to the intracellular region of the channel, we further employed “state-of-the-art” steered molecular dynamics (SMD) simulations. Our SMD simulations revealed two different pathways through which a sodium ion can be expelled from the channel. Further, the SMD simulations identified the key residues that are likely to control these processes. Finally, we discuss the potential binding modes of a panel of known hNav1.5 blockers to our structural model of hNav1.5. We believe that the data presented here will enhance our understanding of the structure–property relationships of the hNav1.5 ion channel and the underlying molecular mechanisms in sodium ion permeation and drug interactions. The results presented here could be useful for designing safer drugs that do not block the hNav1.5 channel.

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Section: Methods and Computational Detailsmentioning

confidence: 99%

Modeling the human Na<sub>v</sub>1.5 sodium channel: structural and mechanistic insights of ion permeation and drug blockade

Ahmed

Hasani

Houghton³

et al. 2017

DDDT

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“…Flecainide is a trifluoroethoxybenzamide approved for the treatment of AF and/or supraventricular tachycardia. Importantly, flecainide is not recommended to patients with underling structural heart disease as the drug can be pro-arrhythmic in this environment ( Andrikopoulos et al, 2015 ). While flecainide is classed as a type IC antiarrhythmic drug (a Na + channel blocker) it is worth noting here the drugs ability to inhibit RyR2 action by reducing the duration of channel opening ( Figure 4 ).…”

Section: Cardiac Arrhythmiasmentioning

confidence: 99%

Targeting Ca2 + Handling Proteins for the Treatment of Heart Failure and Arrhythmias

2020

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Diseases of the heart, such as heart failure and cardiac arrhythmias, are a growing socioeconomic burden. Calcium (Ca 2+) dysregulation is key hallmark of the failing myocardium and has long been touted as a potential therapeutic target in the treatment of a variety of cardiovascular diseases (CVD). In the heart, Ca 2+ is essential for maintaining normal cardiac function through the generation of the cardiac action potential and its involvement in excitation contraction coupling. As such, the proteins which regulate Ca 2+ cycling and signaling play a vital role in maintaining Ca 2+ homeostasis. Changes to the expression levels and function of Ca 2+-channels, pumps and associated intracellular handling proteins contribute to altered Ca 2+ homeostasis in CVD. The remodeling of Ca 2+-handling proteins therefore results in impaired Ca 2+ cycling, Ca 2+ leak from the sarcoplasmic reticulum and reduced Ca 2+ clearance, all of which contributes to increased intracellular Ca 2+. Currently, approved treatments for targeting Ca 2+ handling dysfunction in CVD are focused on Ca 2+ channel blockers. However, whilst Ca 2+ channel blockers have been successful in the treatment of some arrhythmic disorders, they are not universally prescribed to heart failure patients owing to their ability to depress cardiac function. Despite the progress in CVD treatments, there remains a clear need for novel therapeutic approaches which are able to reverse pathophysiology associated with heart failure and arrhythmias. Given that heart failure and cardiac arrhythmias are closely associated with altered Ca 2+ homeostasis, this review will address the molecular changes to proteins associated with both Ca 2+handling and-signaling; their potential as novel therapeutic targets will be discussed in the context of pre-clinical and, where available, clinical data.

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“…The first warning signal for current AADs was the report of the CAST trial results [ 11 , 12 ] demonstrating an increase in mortality with encainide, flecainide and moricizine in patients with structural heart disease. The management of ischemic heart disease changed since then, and flecainide proved to be safer than initially believed [ 13 ]. However, repeated meta-analyses and systematic reviews showed that current AADs have moderate to low efficacy in controlling sinus rhythm at the expense of frequent side effects including severe proarrhythmia and a high withdrawal rate [ 14 ].…”

Section: The Beginning Of the End And The End Of The Beginningmentioning

confidence: 99%

Antiarrhythmic drugs for atrial fibrillation: Imminent impulses are emerging

Dan

Dobrev

2018

IJC Heart & Vasculature

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Rhythm and rate strategies are considered equivalent for the management of atrial fibrillation (AF). Moreover, both strategies are intended for improving symptoms and quality of life. Despite the clinical availability of several antiarrhythmic drugs (AAD) the alternatives for the patient with comorbidities are significantly fewer because of the concern regarding many adverse effects, including proarrhythmias. The impetuous development of AF ablation gave rise to a false impression that AAD are a second line therapy. All these statements reflect, in fact, the weakness of the classical paradigm and classification regarding AAD and the gap between the current knowledge of AF mechanism and determinants and the "classical" AAD non-discriminatory action. A new paradigm in development of effective and safe AAD is based on modern knowledge of vulnerable parameters involved in the genesis and perpetuation of AF. New AAD will target specific triggers of AF and ion currents which are expressed preferentially in fibrillatory atrium. Such targets will include repolarizing currents and channels, as ultrarapid potassium current, two pore potassium current, the acetylcholine-gated potassium current, small-conductance calcium-dependent potassium channels, but, also, molecular targets involved in intracellular calcium kinetics, as Ca2+-calmodulin–dependent protein kinase, ryanodine receptors and non-coding miRNA. New mechanistic discoveries link AF to inflammation and modern anti-cytokine drugs. There is still a long way to win between basic research and clinical practice, but, without any doubt, antiarrhythmic drug therapy will remain and develop as a cornerstone therapy for AF not in conflict, but complementary and alternative to interventional therapy.

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Flecainide: Current status and perspectives in arrhythmia management

Cited by 76 publications

References 58 publications

Modeling the human Na<sub>v</sub>1.5 sodium channel: structural and mechanistic insights of ion permeation and drug blockade

Modeling the human Na<sub>v</sub>1.5 sodium channel: structural and mechanistic insights of ion permeation and drug blockade

Targeting Ca2 + Handling Proteins for the Treatment of Heart Failure and Arrhythmias

Antiarrhythmic drugs for atrial fibrillation: Imminent impulses are emerging

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