The positive frequency-dependent electrophysiological effects of the IKur inhibitor XEN-D0103 are desirable for the treatment of atrial fibrillation

Autor: Erich Wettwer, John Ford, Simone Mueller Loose, Said El Haou, Klaus Matschke, Benoit Tyl, James T. Milnes, Ursula Ravens, Patrick Round
Jazyk: angličtina
Rok vydání: 2016
Předmět:
0301 basic medicine
Male
Refractory Period
Electrophysiological
PLT20
plateau potential
that is
mean absolute membrane potential (mV) in the time window between 20% and 30% of APD90
Action Potentials
030204 cardiovascular system & hematology
APD20
APD50
APD90
action potential duration at 20%
50%
and 90% of repolarization
DMSO
dimethyl sulfoxide
Human atrial action potentials
Electrocardiography
0302 clinical medicine
QTc
Atrial Fibrillation
QTcF
Medicine
Sinus rhythm
cAF
chronic atrial fibrillation
ANOVA
analysis of variance
dV/dtmax
maximum upstroke velocity
HR
heart rate
Effective refractory period
Atrial fibrillation
ECG
electrocardiogram/electrocardiographic
pAF
paroxysmal atrial fibrillation
QT
corrected QT
Healthy Volunteers
3. Good health
Treatment Outcome
Tolerability
Cardiology
QTcF
QT interval corrected by the Fridericia formula
Cardiology and Cardiovascular Medicine
Electrophysiologic Techniques
Cardiac
Anti-Arrhythmia Agents
RMP
resting membrane potential
TMC
time-matched control
Adult
medicine.medical_specialty
AF
atrial fibrillation
QT interval
Article
IKur
ultra-rapidly activating delayed-rectifier potassium current
03 medical and health sciences
Frequency dependence
Physiology (medical)
Internal medicine
Heart rate
Repolarization
Humans
Heart Atria
SR
sinus rhythm
business.industry
APA
action potential amplitude
medicine.disease
030104 developmental biology
ERP
effective refractory period
IKur inhibitor XEN-D0103
AP
action potential
business
Delayed Rectifier Potassium Channels
Zdroj: Heart Rhythm
ISSN: 1556-3871
1547-5271
Popis: Background Selective inhibitors of Kv1.5 channels are being developed for the treatment of atrial fibrillation (AF). Objectives The purpose of this study was to investigate the effects of the highly selective Kv1.5 inhibitor XEN-D0103 on human atrial action potentials (APs) at high excitation rates and to assess safety. Methods Intracellular APs (stimulation rates 1–5 Hz) were measured in right atrial trabeculae from patients in sinus rhythm (SR), chronic AF (cAF; AF of >6 months duration), and paroxysmal AF (pAF). The safety and tolerability of XEN-D0103 were tested in a double-blind, randomized, placebo-controlled phase 1 study. Results Depending on its concentration, XEN-D0103 elevated the plateau potential. At 1 Hz, XEN-D0103 (3 µM) shortened action potential duration at 90% repolarization (APD90) and effective refractory period (ERP) in SR preparations, but prolonged these parameters in cAF preparations. In SR and pAF preparations, the shortening effects on APD90 and ERP turned into prolongation at high rates. In cAF trabeculae, XEN-D0103 prolonged APD90 and ERP at 2 and 3 Hz. At high rates, more SR and pAF preparations failed to capture excitation in the presence of the drug than in its absence. XEN-D0103 (10 µM) did not significantly affect human ventricular APs. Even with plasma concentrations reaching 7000 ng/mL, XEN-D0103 did not increase ∆∆QTcF (QT interval corrected by the Fridericia formula) in the analysis of electrocardiograms of healthy volunteers, and no subjects receiving an active treatment had a QT or QTcF interval >450 ms, or increase in QTcF from baseline >30 ms. Conclusion APD prolongation and suppression of APs by XEN-D0103 at high stimulation rates in SR and pAF tissue, but not cAF, could be of therapeutic benefit for reducing AF burden. This concept needs to be confirmed in clinical trials.
Databáze: OpenAIRE
Externí odkaz: