Investigational antiarrhythmic agents: promising drugs in early clinical development

Abstract

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 Ca²⁺-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.

Keywords: Antiarrhythmic drugs; atrial fibrillation; calcium handling; ion channels; sudden cardiac death.

Figure 1.. Fundamental arrhythmogenic mechanisms and antiarrhythmic therapies.

Ectopic activity, often resulting from delayed or early afterdepolarizations (DADs or EADs, respectively), and reentry, promoted by short and heterogeneous effective refractory periods, Ca²⁺-driven repolarization alternans and slow heterogeneous conduction, are the predominant arrhythmogenic mechanisms involved in the initiation and maintenance of cardiac arrhythmias. Both mechanisms are influenced by interactions between the genetic predisposition, environmental factors, and (non-) cardiovascular diseases. Almost all AADs exhibit both pro- and antiarrhythmic effects. For example, Class I AADs (blocking cardiac Na⁺ channels) decrease excitability, reducing the likelihood of ectopic activity and prolong effective refractory period, reducing reentry, but can promote reentry by slowing conduction velocity. Similarly, Class III AADs prolong effective refractory period, reducing reentry, but can promote EAD-mediated ectopic activity.

Figure 2.. Paradigm shift in antiarrhythmic drug (AAD) therapy.

Most of the currently available AADs were coincidental findings, affect numerous electrophysiological targets and are applied to a heterogeneous group of patients in a ‘one-size-fits-most approach’ (left panel), resulting in limited efficacy and substantial adverse effects including proarrhythmia and extracardiac toxicity. Future ‘precision medicine’ approaches will likely provide a tailored, mechanism-based therapy by a deliberate combination of a number of selective AADs based on individual arrhythmia mechanisms (right panel).