Prosim o preklad lekare, Brugada Syndrome studie

C-TERMINAL SCN5A MUTATION, F2004L, IN BRUGADA
SYNDROME: NEW ARRHYTHMOGENIC CONCEPTS
M. Bébarová
1,2
, T. O ́Hara
3
, J. Geelen
1
, R. Jongbloed
1
, C.
Timmermans
1
, Y. Arens
1
, LM. Rodriguez
1
, Y. Rudy
3
, P. Volders
1
1
Cardiovascular Research Institute
Maastricht, The Netherlands,
2
Department of Physiology, Faculty of Medicine, Masaryk University
Brno, Czech Republic,
3
Cardiac Bioelectricity and Arrhythmia Center,
Washington University in St. Louis, MO, USA.
Two arrhythmogenic mechanisms are generally considered in Brugada
syndrome (BrS): (1) Heterogeneous loss of the epicardial action-
potential (AP) dome in the right ventricle (RV), which generates
transmural dispersion of repolarizati
on resulting in phas
e-2 reentry; (2)
RV outflow tract conduction delay due
to reduced depolarization, also
favoring reentry. Here we report biophysical properties and
arrhythmogenic consequences of a new SCN5A mutation F2004L. The
F2004L mutation was detected in a Dutch kindred. The proband, a 26-
year old male, experienced syncope
and had coved-type ST elevations
in ECG leads V1 and V2. QRS width was 135 ms. Functional
consequences of the mutation were studied in transfected CHO cells by
whole-cell patch clamping. Peak Na
+
current (
I
Na
) was reduced to 54%
compared to wild type (WT; V
hold
–120 mV). Persistent tetrodotoxin-
sensitive
I
Na
was reduced to 56%. F2004L channels showed increased
closed-state and slow inactivation.
Recovery from inactivation was also
slowed (e.g., fast tau 49±8 ms in F2004L vs. 20±4 ms in WT at V
hold
–
80 mV,
p
<0.05). Electrophysiological characteristics of F2004L and
WT currents were introduced in a math
ematical model of the transmural
RV wedge. In the mutant model, the excitation wave was decremental
from endo- to epicardium, and eventually died out at cycle length (CL)
1000 ms (but not at CL 300 ms). Propagation continued, however, by
phase-2 conduction causing long de
lays of excitation and slow
upstrokes at the epicardium. We hypothesize that the observed
transmural decrement and epicardial
loss of excitation in the RV was
caused by a gradual decrease of
I
Na
(slow depolarization
→
increased
closed-state inactivation of
I
Na
→
decreased availability of
I
Na
channels)
and the physiological increase of transient outward K
+
current towards
the epicardium. Our data may explain ST-segment elevation on the
basis of massive transmural voltage gradients during early
repolarization. Reentry-based t
achycardia could be evoked during
conditions that further exaggera
te conduction block in this BrS
phenotype.
Supported by grants No. MSM0021622402 and RO1-HL49054, and
Merit Award R37-HL33343