Innovative Therapeutics for Atrial Fibrillation

Atrial fibrillation (AF) is the most common sustained arrhythmia in clinical practice, estimated to affect about 1 in 4 individuals over their lifetime.1 Its prevalence is rising rapidly, projected to rise to around 15,000,000 in the United States by 2050.1 At the same time, the treatment of AF is suboptimal. Antiarrhythmic drugs have limited efficacy and undesirable side effects. Ablation is likely more effective but has nontrivial risks and costs, limited applicability in the very large AF population and is plagued by long-term recurrences. While new anticoagulants are finally replacing rat-poison (a common nonmedical application of warfarin) for stroke prevention they have bleeding risks and cost issues of their own. Drug therapy for AF has been around for a long time. Digitalis, which has been used to treat the arrhythmia for hundreds of years, is still in use, although debates about its risk and appropriate use remain very active.2 Research on AF mechanisms, designed ultimately to innovate therapy, has also been very active,3,43,4 where has it gotten us? We have been talking about new developments in AF management for at least 20 years.5 In 1995, the main issues were the relative value of rate versus rhythm management, the potential for ablation therapy (which at that time was very primitive and largely ineffective) and controversies about the use of oral anticoagulation.5 Looking back over the ensuing 20 years, one would have to concede that there has been dramatic evolution on all fronts. Ablation therapy, driven by both careful clinical observation and scientific advances, has taken a major place in AF management.6 The rate versus rhythm control debate has been resolved, at least with contemporary approaches, as a draw in large well-designed clinical trials.7,87,8 Anticoagulation therapy has been revolutionized, on one hand by novel oral anticoagulants that are substantially safer than vitamin K antagonists,9 and on the other hand by modern risk-scoring systems that have put rational decision making on a solid empirical basis.10 Despite these great advances, much remains to be done to improve AF therapy. The drugs available for sinus rhythm maintenance are largely limited to agents discovered over 30 years ago.11 Although AF ablation has advanced greatly, its value as first-line therapy continues to be unclear.12,1312,13 AF-related strokes continue to be a major problem and there is continued concern about underuse of oral anticoagulation.14 It is in this context that the Journal of Cardiovascular Pharmacology has put together a review series on emerging treatments for AF. The first 2 articles in the series discuss new drug approaches that target classical ion-channel determinants of AF. El-Haou et al15 deal with novel K+-channel blocking drugs. The authors review the rationale, basic and clinical pharmacology, and state of development of a variety of agents inhibiting K+-channels like those underlying the ultra-rapid delayed rectifier current (IKur),16 the acetylcholine-regulated K+-current (IKACh),17 small-conductance Ca2+-dependent K+-currents (IKCa),18 and 2-pore-domain K+-currents (IK2p).19 Aguilar and Nattel then review the role of Na+-channel blockers in AF.20 The authors begin with a historical account of their use for the arrhythmia. They then move on to discuss the enigma of their efficacy, because conduction slowing is classically considered to promote, rather than terminate, AF and explain how spiral-wave theory explains AF-termination by Na+-channel blockers through destabilization of arrhythmia-generating rotors. They conclude with a discussion of how mathematical analysis can be used to identify the pharmacodynamic properties of agents designed to produce drugs with optimized efficacy/risk ratios, through highly-selective actions during AF with little or no effect in sinus rhythm. Diness et al then follow with a detailed presentation of the role of IKCa in AF and the potential value of drugs blocking this current as novel antiarrhythmics.21 The next series of articles discuss pharmacological strategies that do not target ion-channels. Heijman et al review the potential value of agents designed to normalize cardiomyocyte Ca2+-handling.22 Recent studies indicate that aberrant Ca2+-handling likely underlies the ectopic atrial firing that often initiates, and may even sustain, AF in man.23,2423,24 The authors consider various strategies related to the role of intracellular Ca2+ in AF, including sarcolemmal Ca2+-channels, sarcoplasmic-reticulum Ca2+-channels (ryanodine receptor channels), the Na+, Ca2+-exchanger, the sarcoplasmic-reticulum Ca2+-uptake pump, Ca2+-dependent sarcolemmal channels, and Ca2+-dependent remodeling processes.25 Gutierrez et al then consider the value of therapies targeting oxidative pathways and inflammatory mechanisms in AF.26 They update readers on the most recent basic science developments in this area, including results that point to new targets like deranged proteostasis and toxic amyloid precursors. Hammwöhner and Goette entertain the proposition that, with the advent of the novel direct-acting oral anticoagulants (commonly called “NOACs”), perhaps all AF-patients should be anticoagulated to prevent strokes.27 Their conclusion is that bleeding risks exceed the benefits in low stroke-risk patients, but that the situation may change if, as expected effective antidotes to reverse NOAC-effects can be developed. The final series of articles discuss rapidly-evolving innovative approaches to AF-management. Junaid et al review the increasingly-important application of atrial ablation procedures to control AF, particularly with the advent of techniques that target specific AF-initiating or AF-maintaining mechanisms.28 Darbar discusses the potential value of genomic data in guiding AF therapy.29 He points out how genetic studies have provided novel insights into the molecular basis of clinical AF, and reviews the available data regarding genotype-specific therapeutic responses. Although the future for gene-directed management appears promising, major challenges remain and pharmacogenomic guidance remains a promising but as yet unrealized strategy to improve the treatment of AF. Finally,30 Donahue discusses the present state of biological therapy development. He reviews the principles of gene-delivery and their application, and then discusses the targets under development, including rate-control, rhythm-control, and thromboresistance. Interestingly, biological therapies are the only approach thus far reported to suppress AF in animal models by effectively reversing conduction abnormalities caused by connexin remodeling.31,3231,32 Whether the promise of such treatments can be effectively translated to clinical practice remains to be seen. A comparison of the present series with the previous review series in the Journal 7 years ago33 is both exciting and sobering. The clinical use of certain approaches, like AF-ablation and NOACs, has seen important advances. The targeting of novel K+-channels has seen significant development in terms of the introduction of new drugs and their testing in man, although none have yet been approved for clinical use outside of investigational trials. The other areas reviewed have advanced in terms of new basic science knowledge, the identification of novel pharmacological tools and targets, and limited testing of concepts in human tissues and databases, but direct practical applications remain a goal rather than a reality. Hopefully, by the time the next review series on novel AF management is published in this journal, many more of the approaches reviewed here will have arrived into clinical practice and will have improved the care of patients with this challenging arrhythmia.

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