The Role of Pharmacogenetics in Atrial Fibrillation Therapeutics

Darbar, Dawood

doi:10.1097/fjc.0000000000000280

Cited by 16 publications

(17 citation statements)

References 126 publications

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“…These variants frequently require further classification to confirm or eliminate their pathogenicity. Genetic predisposition may influence the response to AF therapies (Darbar et al, 2007 ; Parvez et al, 2012 ; Benjamin Shoemaker et al, 2013 ; Huang and Darbar, 2016 ) and can allow specific and based-mechanism therapies (Roberts and Gollob, 2010 ; Campbell et al, 2013 ; Faggioni et al, 2014 ; Darbar, 2016 ).…”

Section: Af Pathophysiologymentioning

confidence: 99%

Atrial Fibrillation Mechanisms and Implications for Catheter Ablation

et al. 2018

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AF is a heterogeneous rhythm disorder that is related to a wide spectrum of etiologies and has broad clinical presentations. Mechanisms underlying AF are complex and remain incompletely understood despite extensive research. They associate interactions between triggers, substrate and modulators including ionic and anatomic remodeling, genetic predisposition and neuro-humoral contributors. The pulmonary veins play a key role in the pathogenesis of AF and their isolation is associated to high rates of AF freedom in patients with paroxysmal AF. However, ablation of persistent AF remains less effective, mainly limited by the difficulty to identify the sources sustaining AF. Many theories were advanced to explain the perpetuation of this form of AF, ranging from a single localized focal and reentrant source to diffuse bi-atrial multiple wavelets. Translating these mechanisms to the clinical practice remains challenging and limited by the spatio-temporal resolution of the mapping techniques. AF is driven by focal or reentrant activities that are initially clustered in a relatively limited atrial surface then disseminate everywhere in both atria. Evidence for structural remodeling, mainly represented by atrial fibrosis suggests that reentrant activities using anatomical substrate are the key mechanism sustaining AF. These reentries can be endocardial, epicardial, and intramural which makes them less accessible for mapping and for ablation. Subsequently, early interventions before irreversible remodeling are of major importance. Circumferential pulmonary vein isolation remains the cornerstone of the treatment of AF, regardless of the AF form and of the AF duration. No ablation strategy consistently demonstrated superiority to pulmonary vein isolation in preventing long term recurrences of atrial arrhythmias. Further research that allows accurate identification of the mechanisms underlying AF and efficient ablation should improve the results of PsAF ablation.

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Section: Af Pathophysiologymentioning

confidence: 99%

Atrial Fibrillation Mechanisms and Implications for Catheter Ablation

et al. 2018

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“…Ideally, such electrophysiological differences can be exploited in the future to improve the efficacy and safety of AAD therapy. For example, initial data have suggested that pharmacogenetic-guided selection of Class I vs. Class III drugs in patients with AF may improve the response to AAD therapy [39, 40]. This approach is currently being tested in a preliminary feasibility study (NCT02347111).…”

Section: General Considerations For Novel Antiarrhythmic Drugsmentioning

confidence: 99%

“…A large number of potential antiarrhythmic targets and agents have been discussed in a number of excellent recent review articles. For example, several reviews have focused on atrial-selective K + -channel blockers for AAD therapy in AF [34, 35, 36], AADs against atrial and ventricular arrhythmias targeting Ca 2+ -handling abnormalities [42, 43], or personalization of AAD therapy [40]. Here, we focus on several targets and the agents directed against these targets that have received considerable attention during the last few years.…”

Section: Promising Antiarrhythmic Targets and Agentsmentioning

confidence: 99%

Investigational antiarrhythmic agents: promising drugs in early clinical development

Heijman

Ghezelbash

Dobrev

2017

Expert Opinion on Investigational Drugs

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Although there have been important technological advances for the treatment of cardiac arrhythmias (e.g., catheter ablation technology), antiarrhythmic drugs (AADs) remain the cornerstone therapy for the majority of patients with arrhythmias. Most of the currently available AADs were coincidental findings and did not result from a systematic development process based on known arrhythmogenic mechanisms and specific targets. During the last 20 years, our understanding of cardiac electrophysiology and fundamental arrhythmia mechanisms has increased significantly, resulting in the identification of new potential targets for mechanism-based antiarrhythmic therapy. Areas covered: Here, we review the state-of-the-art in arrhythmogenic mechanisms and AAD therapy. Thereafter, we focus on a number of antiarrhythmic targets that have received significant attention recently: atrial-specific K-channels, the late Na-current, the cardiac ryanodine-receptor channel type-2, and the small-conductance Ca-activated K-channel. We highlight for each of these targets available antiarrhythmic agents and the evidence for their antiarrhythmic effect in animal models and early clinical development. Expert opinion: Targeting AADs to specific subgroups of well-phenotyped patients is likely necessary to detect improved outcomes that may be obscured in the population at large. In addition, specific combinations of selective AADs may have synergistic effects and may enable a mechanism-based tailored antiarrhythmic therapy.

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“…However, even for a given AF type, there is substantial patient-to-patient variability in the clinical presentation, ranging from numerous short-lived AF episodes to few but long-lasting episodes, and from completely asymptomatic to severely symptomatic patients [1,5] Challenges to the translation of basic science findings to atrial fibrillation therapies EDitORial of AF complexity may facilitate a more stratified approach. ECG biomarkers of AF complexity can predict long-term success of catheter ablation [16] and tailored therapy based on genetic information might also be possible and is currently being evaluated based on genetic variants near the PITX2 gene [17]. Nonetheless, extrapolating genetic alterations to AF mechanisms in patients remains challenging.…”

Section: • • the Etiology Of Af Patients Is Highly Heterogeneousmentioning

confidence: 99%