Atrial fibrillation therapy now and in the future: drugs, biologicals, and ablation

Abstract

Atrial fibrillation (AF) is a complex disease with multiple inter-relating causes culminating in rapid, seemingly disorganized atrial activation. Therapy targeting AF is rapidly changing and improving. The purpose of this review is to summarize current state-of-the-art diagnostic and therapeutic modalities for treatment of AF. The review focuses on reviewing treatment as it relates to the pathophysiological basis of disease and reviews preclinical and clinical evidence for potential new diagnostic and therapeutic modalities, including imaging, biomarkers, pharmacological therapy, and ablative strategies for AF. Current ablation and drug therapy approaches to treating AF are largely based on treating the arrhythmia once the substrate occurs and is more effective in paroxysmal AF rather than persistent or permanent AF. However, there is much research aimed at prevention strategies, targeting AF substrate, so-called upstream therapy. Improved diagnostics, using imaging, genetics, and biomarkers, are needed to better identify subtypes of AF based on underlying substrate/mechanism to allow more directed therapeutic approaches. In addition, novel antiarrhythmics with more atrial specific effects may reduce limiting proarrhythmic side effects. Advances in ablation therapy are aimed at improving technology to reduce procedure time and in mechanism-targeted approaches.

Keywords: arrhythmias, cardiac; atrial fibrillation; catheter ablation.

Figure 1

Rhythm control strategies. Algorithm for treatment decision for antiarrhythmic and ablation to maintain sinus rhythm in patients with paroxysmal or persistent atrial fibrillation. Drugs are listed alphabetically within boxes. *Dronedarone should not be used in patients with long-standing persistent or permanent AF (see text for details). CAD=coronary artery disease. LVH=left ventricular hypertrophy. Ablation can also be considered upfront prior to failed antiarrhythmic medications (class IIa indication) (Modified from Wan et al. Circulation 2011).

Figure 2

Remodeling mechanisms in AF. In red are listed potential drug targets. Further details can be found in Tables 2 and 3, and in the text. TGF (transforming growth factor)- β, HSP (heat shock protein), HDAC (Histone deacetylase-6), RAAS (renin-angiotensin-aldosterone system), CAMK (calcium-calmodulin-kinase)-II, L-type (dihyropyridine receptor), RyR (ryanodine recptor-2), PKC (protein kinase C)- ε.

Figure 3

Emerging imaging modalities for AF. A. MRI based fibrosis imaging of the atria showing the University of Utah Atrial Fibrillation LGE-MRI-based staging system in human. Green areas indicate areas of fibrosis. (adapted from Vergara et al, J Cardiovasc Electrophysiol, Vol. pp. 1-7 2010). B. Left atrial rotor with counterclockwise activation in human mapped computationally using the proprietary FIRM system (RhythmView, Topera Medical, Lexington, Massachusetts).(adapted J Am Coll Cardiol 2012;60: 628–36 2012). C. Phase mapping of posterior human left atrium during paroxysmal AF showing two successive rotations of a rotor near the right PV ostia using 252-electrode vest was applied to the patient’s torso for body-surface mapping. The core of the rotor is depicted with a white star. The phases of the voltage propagation period are color-coded with blue representing the depolarizing period, and green representing the end of the repolarization (adapted from Haissaguerre et al. J Cardiovasc Electrophysiol, Vol. 24, pp. 711-717, June 2013). D. Endoscopic optical mapping of pulmonay vein (top left) and left ventricle (top right) in swine-isolated heart with a balloon tipped catheter via transeptal approach. Propagation map at successive time points from ventricular image for one beat shown below (unpublished data, Woods CE, 2013, courtesy of AUST Development, LLC).

Figure 4

Current Approaches to AF ablation. A-D Schematic drawing of the left and right atria as viewed from the posterior showing common approaches to AF ablation. In some cases, more than one approach (or combination of approaches in a stepwise fashion) are performed. A. Wide Area Circumferential Ablation—Antral Pulmonary Vein Isolation. Ablation of the pulmonary vein antra to electrically isolate pulmonary veins. Wide area ablation also isolates a large portion of the posterior left atria within the circumferential ablation. Variations on this ablation include isolation of each PV antrum separately as opposed to combination isolation of ipsilateral veins. Endpoints for ablation are bi-directional conduction block into and out of pulmonary veins and intact circumferential lesions. B. Pulmonary Vein Segmental Ostial Ablation. Ablation of each PV ostium is done to achieve the same endpoints as in A. but without complete empirical ablation around the vein and includes less of the antrum. C. Linear Ablation. In some instances (typically in persistent AF or as part of a step-wise approach in subsequent ablations following recurrence), linear lesions are added to pulmonary vein isolation. These are typically roof-lines and mitral annular ablation. Addition of these ablation lines significantly increases the risk of post-procedure atrial flutter. Confirmation of integrity and completeness of the line is important to minimize atrial flutter occurrence. Additional variations are also depicted showing a “roof line” connection the left and right PVs, “mitral isthmus” line connecting the mitral valve to the lesion set around the left PV, anterior line connecting the roof lesion set to the mitral annulus, cavotricuspid isthmus line, figure of 8 lesion set including carinal lesions, and ablation to isolate the SVC. D: Complex Fractionated Electrogram (CFE) Ablation. Common sites of complex fractionated electrograms are shown in the figure and an example of a CFE. E. Ganglionic Plexi Ablation. The left atrial autonomic ganglionic plexi (GP) and axons (superior left GP,inferior left GP, anterior right GP, inferior right GP, and ligament of Marshall) are shown in gray. The coronary sinus and ligament of Marshall are shown in hatched gray. Ablation of GP’s is performed either by empiric ablation over these areas or by mapping using high-frequency stimulation to identify areas that result in a vagal effect. F: Rotor Ablation. Rotors are depicted by large and small gray rotating lines. Stable, “driving” rotors are targeted by novel mapping approaches for ablation. (adapted from 2012 HRS/EHRA/ECAS Expert Consensus)