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  • Review Article
  • Published:

Novel molecular targets for atrial fibrillation therapy

Key Points

  • Atrial fibrillation (AF) is the most common form of cardiac arrhythmia. It represents a major health problem and causes substantial morbidity and mortality in the general population.

  • Despite recent therapeutic advances, current pharmacological treatments have modest efficacy and substantial risks, making the development of new therapeutic strategies crucial.

  • There is a clear unmet need to develop novel mechanistically based therapeutic options with improved efficacy and favourable safety profiles.

  • In recent years, substantial efforts have been invested in developing treatments that target the underlying mechanisms of AF, and several new compounds are under development.

  • In this Review, we discuss the mechanistic rationale for the development of new anti-AF drugs, the molecular and structural motifs that they target, and the results obtained in experimental and clinical studies.

  • New insights into the mechanisms underlying AF have identified promising new approaches, including the modulation of atrium-specific ion channels, connexins and the ryanodine receptor, the prevention of remodelling processes that lead to the arrhythmia as well as specific molecular events involved in arrhythmia generation.

  • The validation of newer approaches based on microRNA targeting and gene therapy strategies, as well as the discovery of novel pathophysiological mechanisms and targets through genetic technology, may lead to the development of additional novel AF therapies.

Abstract

Atrial fibrillation is the most common type of cardiac arrhythmia, and is responsible for substantial morbidity and mortality in the general population. Current treatments have moderate efficacy and considerable risks, especially of pro-arrhythmia, highlighting the need for new therapeutic strategies. In recent years, substantial efforts have been invested in developing novel treatments that target the underlying molecular determinants of atrial fibrillation, and several new compounds are under development. This Review focuses on the mechanistic rationale for the development of new anti-atrial fibrillation drugs, on the molecular and structural motifs that they target and on the results obtained so far in experimental and clinical studies.

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Figure 1: General mechanisms of AF and role of ion channels for AF stabilization.
Figure 2: Molecular basis for atrial ionic remodelling and therapeutic opportunities.
Figure 3: Molecular basis for Ca2+-related arrhythmic activity in AF, and possible molecular targets.
Figure 4: K+ channel structure-based blocking drugs.
Figure 5: Connexin-targeted drugs.
Figure 6: Drugs targeting ryanodine receptor function through improved FKBP12.6 binding and domain zipping.
Figure 7: Ion channel bioprocessing and trafficking as potential targets for drug development.

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Bianca J. J. M. Brundel, Xun Ai, … Natasja M. S. de Groot

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Acknowledgements

D.D. received support from the European Union through the European Network for Translational Research in Atrial Fibrillation (EUTRAF; grant no. 261057), the German Federal Ministry of Education and Research via the Atrial Fibrillation Competence Network (01GI0204) and the German Center for Cardiovascular Research, as well as the Deutsche Forschungsgemeinschaft (Do 769/1-3). S.N. is supported by grants from the Canadian Institutes of Health Research (MOP-44365 and MGP-6957) and the Quebec Heart and Stroke Foundation. D.D. and S.N. are co-principal investigators of the European/North American Atrial Fibrillation Research Alliance (ENAFRA; no. 07CVD03) network grant of Fondation Leducq. O. Fjellström, Medicinal Chemistry, AstraZeneca R&D, Sweden, is acknowledged for the illustration of the inwardly rectifying K+ channel depicted in Figure 4a.

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Correspondence to Dobromir Dobrev or Stanley Nattel.

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Competing interests

D.D. has received consulting fees/honoraria from: BIOTRONIK, AstraZeneca, Boehringer Ingelheim, Merck Sharpe & Dohme and Sanofi. Travel support has been provided by the European Heart Rhythm Association and the European Society of Cardiology.

S.N. has been a consultant for Cardiome Pharma, Bayer/Schering Pharma, St Jude Medical and Merck Pharmaceuticals. His invited lectures have been sponsored by Biosense Webster, Sanofi Aventis and Pfizer. He has received research grants from AstraZeneca Pharmaceuticals and Xention Discovery. He is also an inventor on patents belonging to the Montreal Heart Institute.

L.C. declares no competing financial interests.

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FURTHER INFORMATION

ClinicalTrials.gov website (list results for search 'GAP-134')

ClinicalTrials.gov website (list results for search 'K201')

Glossary

Congestive heart failure

A condition in which the suboptimal performance of cardiac muscle leads to reduced cardiac output (causing fatigue and inadequate organ perfusion) as well as retention of salt and water, causing ankle swelling and shortness of breath owing to interstitial fluid accumulation in the lungs.

Ischaemic heart disease

A condition in which narrowing of the coronary arteries leads to inadequate blood supply to cardiac muscle, causing chest pain on exertion. When an artery is completely blocked, it causes myocardial necrosis or infarction, commonly called a heart attack.

Cardioversion

Termination of atrial fibrillation by applying an electrical shock to stop the arrhythmia and allow the normal heart pacemaker to take over.

Sinus rhythm

The normal cardiac rhythm resulting from regular firing of pacemaker cells in the sinus node of the heart.

Phospholamban

(PLN). An inhibitor of cardiac muscle sarcoendoplasmic reticulum Ca2+ ATPase (Serca) in the unphosphorylatedstate. PLN phosphorylation disinhibits SERCA and increases Ca2+ uptake into the sarcoplasmic reticulum.

Ventricular pro-arrhythmia

The paradoxical induction or worsening of ventricular arrhythmias by drugs used to treat arrhythmias.

Class I anti-arrhythmic drug

A drug that suppresses arrhythmias by blocking cardiac Na+ channels.

Mitral regurgitation

A condition in which the mitral valve, which is located between the left atrium and left ventricle, is leaky, causing blood to back up and engorge the left atrium; this leads to atrial damage and eventually to atrial fibrillation.

Pacing-induced AF

Atrial fibrillation (AF) initiated by a rapid burst of firing from an artificial pacemaker in the atrium, which exposes a tissue anomaly, usually resulting from remodelling, that allows an arrhythmia to be sustained.

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Dobrev, D., Carlsson, L. & Nattel, S. Novel molecular targets for atrial fibrillation therapy. Nat Rev Drug Discov 11, 275–291 (2012). https://doi.org/10.1038/nrd3682

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