What is the clinical evidence from this study?

Study design: Other. Population: Atrial fibrillation and sinus rhythm (n=44). Intervention: MK-0448 vs. Pre-drug control. Primary outcome: Action potential duration at 90% repolarization (APD90) in sinus rhythm preparations (p=<0.05).

What does this research mean for the field?

The Kv1.5 channel blocker MK-0448 shortens action potential duration in right atrial preparations from patients in sinus rhythm, but prolongs it in preparations from patients with permanent atrial fibrillation. Novelty: ClaimNovelty.INCREMENTAL. Consensus alignment: ConsensusAlignment.NEUTRAL.

March 4, 2014Open Access

Effects of IKur blocker MK-0448 on human right atrial action potentials from patients in sinus rhythm and in permanent atrial fibrillation

Q: What are the key findings of this study?

MK-0448 (3 μM) shortened action potential duration at 90% repolarization from 318.2 to 265.3 ms in sinus rhythm preparations, but prolonged it from 218.3 to 275.0 ms in permanent atrial fibrillation.

Q: What does this research mean for the field?

The Kv1.5 channel blocker MK-0448 shortens action potential duration in right atrial preparations from patients in sinus rhythm, but prolongs it in preparations from patients with permanent atrial fibrillation. Novelty: ClaimNovelty.INCREMENTAL. Consensus alignment: ConsensusAlignment.NEUTRAL.

Key Result

MK-0448 (3 μM) shortened action potential duration at 90% repolarization from 318.2 to 265.3 ms in sinus rhythm preparations, but prolonged it from 218.3 to 275.0 ms in permanent atrial fibrillation.

Structured PICO

Does the Kv1.5 blocker MK-0448 alter action potential duration and effective refractory period in human right atrial trabeculae from patients with different atrial rhythms?

Population

Human right atrial trabeculae from patients in sinus rhythm (SR), permanent atrial fibrillation (> 6 months), and intermittent AF, as well as an expression system.

Intervention

MK-0448 (Kv1.5 blocker) at concentrations including 3 µM

Comparator

Baseline/control (comparing effects across different underlying rhythms)

Outcome

Action potential duration at 90% of repolarization (APD90) and effective refractory period (ERP)surrogate

MK-0448 exerts differential electrophysiological effects depending on the underlying rhythm, prolonging APD90 and ERP in permanent AF but shortening them in sinus rhythm, likely due to additional IKs blockade.

Main Result

Absolute Event Rate: 265.3% vs 318.2%

p-value: p=<0.05

Limitations

In some human atrial preparations, APD does not remain stable during prolonged superfusion with saline solutions
The classification of patients into SR and AF may not always be reliable, as the SR group may include patients with unrecognized episodes of paroxysmal AF

Abstract

Selective blockers of the Kv1. 5 channel have been developed for the treatment of atrial fibrillation (AF), but little is known how these atrial-selective drugs affect human action potentials (APs). Therefore we have investigated the Kv1. 5 blocker MK-0448 (N-6- (1S) -1- (4-fluorophenyl) -2, 2-di (pyridin-3-yl) ethylpyridin-2-ylmethanesulfonamide) in right atrial trabeculae from patients in sinus rhythm (SR), permanent AF (> 6 months), and intermittent AF. MK-0448 blocked Kv1. 5 current in an expression system and concentration-dependently elevated the plateau phase of atrial APs. In SR preparations stimulated at 1 Hz, MK-0448 (3 µM) shortened action potential duration at 90% of repolarization (APD90) and effective refractory period (ERP), but in permanent AF preparations, MK-0448 prolonged APD90 and ERP. The effects of MK-0448 in intermittent AF resembled those in SR preparations. The APD-prolonging effect in AF preparations was more pronounced than with other IKur blockers, most likely due to the additional blocking effect of MK-0448 on IKs, a current that is present both in the atrium and ventricle. Block of IKs is probably more prominent in AF because of reduced repolarization reserve due to AF-induced remodeling.

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