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2014 ; 11
(11
): 2064-72
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Cellular mechanism of premature ventricular contraction-induced cardiomyopathy
#MMPMID25046857
Wang Y
; Eltit JM
; Kaszala K
; Tan A
; Jiang M
; Zhang M
; Tseng GN
; Huizar JF
Heart Rhythm
2014[Nov]; 11
(11
): 2064-72
PMID25046857
show ga
BACKGROUND: Frequent premature ventricular contractions (PVCs) are associated
with increased risk of sudden cardiac death and can cause secondary
cardiomyopathy. OBJECTIVE: We sought to determine the mechanism(s) responsible
for prolonged refractory period and left ventricular (LV) dysfunction
demonstrated in our canine model of PVC-induced cardiomyopathy. METHODS: Single
myocytes were isolated from LV free wall of PVC and control canines and used for
patch-clamp recording, intracellular Ca(2+) measurements, and
immunocytochemistry/confocal microscopy. LV tissues adjacent to the area of
myocyte isolation were used for the immunoblot quantification of protein
expression. RESULTS: In the PVC group, LV ejection fraction decreased from 57.6%
± 1.5% to 30.4% ± 3.1% after ?4 months of ventricular bigeminy. Compared to
control myocytes, PVC myocytes had decreased densities of both outward (transient
outward current [Ito] and inward rectifier current [IK1]) and inward (L-type Ca
current [ICaL]) currents, but no consistent changes in rapid or slow delayed
rectifier currents. The reduction in Ito, IK1, and ICaL was accompanied by
decreased protein levels of their channel subunits. The extent of reduction in
Ito, IK1, and ICaL varied among PVC myocytes, creating marked heterogeneity in
action potential configurations and durations. PVC myocytes showed impaired
Ca-induced Ca release from the sarcoplasmic reticulum (SR), without increase in
SR Ca leak or decrease in SR Ca store. This was accompanied by a decrease in dyad
scaffolding protein, junctophilin-2, and loss of Cav1.2 registry with
Ca-releasing channels (ryanodine receptor 2). CONCLUSION: PVCs increase
dispersion of action potential configuration/duration, a risk factor for sudden
cardiac death, because of the heterogeneous reduction in Ito, IK1, and ICaL. The
excitation-contraction coupling is impaired because of the decrease in ICaL and
Cav1.2 misalignment with respect to ryanodine receptor 2.
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