Why translation from basic discoveries to clinical applications is so difficult for atrial fibrillation and possible approaches to improving it

Abstract

Atrial fibrillation (AF) is the most common sustained clinical arrhythmia, with a lifetime incidence of up to 37%, and is a major contributor to population morbidity and mortality. Important components of AF management include control of cardiac rhythm, rate, and thromboembolic risk. In this narrative review article, we focus on rhythm-control therapy. The available therapies for cardiac rhythm control include antiarrhythmic drugs and catheter-based ablation procedures; both of these are presently neither optimally effective nor safe. In order to develop improved treatment options, it is necessary to use preclinical models, both to identify novel mechanism-based therapeutic targets and to test the effects of putative therapies before initiating clinical trials. Extensive research over the past 30 years has provided many insights into AF mechanisms that can be used to design new rhythm-maintenance approaches. However, it has proven very difficult to translate these mechanistic discoveries into clinically applicable safe and effective new therapies. The aim of this article is to explore the challenges that underlie this phenomenon. We begin by considering the basic problem of AF, including its clinical importance, the current therapeutic landscape, the drug development pipeline, and the notion of upstream therapy. We then discuss the currently available preclinical models of AF and their limitations, and move on to regulatory hurdles and considerations and then review industry concerns and strategies. Finally, we evaluate potential paths forward, attempting to derive insights from the developmental history of currently used approaches and suggesting possible paths for the future. While the introduction of successful conceptually innovative new treatments for AF control is proving extremely difficult, one significant breakthrough is likely to revolutionize both AF management and the therapeutic development landscape.

Keywords: Antiarrhythmic drugs; Atrial fibrillation; Mechanisms; Personalized therapy; Remodelling.

Graphical abstract

Figure 1

Overall AF treatment strategy schema. This is a simplified schema of the main steps in AF management. Haemodynamic stability must first be ensured, and any precipitators or comorbidities addressed. Anticoagulation is an essential early step in almost all patients to prevent thromboembolic complications. Rate control must be established, even in most patients for whom the primary approach will be rhythm control, since pharmacological rhythm control is not foolproof and rhythm-control drugs can cause a paradoxical acceleration in ventricular rate. The choice between rate control and rhythm control as the principal strategy is based on a variety of patient-specific considerations.

Figure 2

Most commonly used AF rhythm-control drugs (A) and a timeline showing their FDA approval year (B). In (A), the drugs are organized in alphabetical order. The detailed clinical decision-making approach for selection of these drugs is complex and not dealt with in this article. CAD, coronary artery disease; HF, heart failure.

Figure 3

Evolution of success rates of catheter ablation of AF over time. Results shown are those obtained in a meta-analysis by Perino et al. (with permission from American Heart Journal and Elsevier). (A) Results for paroxysmal AF; (B) results for persistent AF. Regression lines suggest adjusted mean improvement rates (dashed lines) that were 1%/year for paroxysmal and 1.4%/year for persistent AF-ablations.

Figure 4

Present development pipeline for AF antiarrhythmic agents in the pharmaceutical industry. The agent being developed is shown at the left, followed by the originating entity, a description of the product and the present developmental stage. CaMKII, calcium/calmodulin dependent protein-kinase type II; I_K,ACh, acetylcholine-gated potassium channel; Na⁺ channel, sodium channel; NOX4, NADPH oxidase type 4; RyR2, ryanodine receptor type 2; SK channel, small-conductance calcium-dependent potassium channel; UCLA, University of California at Los Angeles.

Figure 5

Summary of principal preclinical AF-models. Left: manipulations used to create experimental models of AF. Right: principal species in which various types of preclinical models have been created. CMs, cardiomyocytes; HF, heart failure; hIPSCs, human induced pluripotent stem cell; MI, myocardial infarction; NGF, nerve growth factor.

Figure 6

Principal currently used therapies for AF rhythm control (left) and their developmental origins (right). (A) Antiarrhythmic drugs. (B) Interventional methods.