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Articles
by
Y. H Yeh |
Total Records (
3 ) for
Y. H Yeh |
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B Burstein
,
P Comtois
,
G Michael
,
K Nishida
,
L Villeneuve
,
Y. H Yeh
and
S. Nattel
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Rationale: Although connexin changes are important for the ventricular arrhythmic substrate in congestive heart failure (CHF), connexin alterations during CHF-related atrial arrhythmogenic remodeling have received limited attention.
Objective: To analyze connexin changes and their potential contribution to the atrial fibrillation (AF) substrate during the development and reversal of CHF.
Methods and Results: Three groups of dogs were studied: CHF induced by 2-week ventricular tachypacing (240 bpm, n=15); CHF dogs allowed a 4-week nonpaced recovery interval after 2-week tachypacing (n=16); and nonpaced sham controls (n=19). Left ventricular (LV) end-diastolic pressure and atrial refractory periods increased with CHF and normalized on CHF recovery. CHF caused abnormalities in atrial conduction indexes and increased the duration of burst pacing-induced AF (DAF, from 22±7 seconds in control to 1100±171 seconds, P<0.001). CHF did not significantly alter overall atrial connexin (Cx)40 and Cx43 mRNA and protein expression levels, but produced Cx43 dephosphorylation, increased Cx40/Cx43 protein expression ratio and caused Cx43 redistribution toward transverse cell-boundaries. All of the connexin-alterations reversed on CHF recovery, but CHF-induced conduction abnormalities and increased DAF (884±220 seconds, P<0.001 versus control) remained. The atrial fibrous tissue content increased from 3.6±0.7% in control to 14.7±1.5% and 13.3±2.3% in CHF and CHF recovery, respectively (both P<0.01 versus control), with transversely running zones of fibrosis physically separating longitudinally directed muscle bundles. In an ionically based action potential/tissue model, fibrosis was able to account for conduction abnormalities associated with CHF and recovery.
Conclusions: CHF causes atrial connexin changes, but these are not essential for CHF-related conduction disturbances and AF promotion, which are rather related primarily to fibrotic interruption of muscle bundle continuity. |
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X Qi
,
Y. H Yeh
,
D Chartier
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L Xiao
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Y Tsuji
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B. J.J.M Brundel
,
I Kodama
and
S. Nattel
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Background— Sustained bradycardia is associated with long-QT syndrome in human beings and causes spontaneous torsades de pointes in rabbits with chronic atrioventricular block (CAVB), at least partly by downregulating delayed-rectifier K+-current to cause action potential (AP) prolongation. We addressed the importance of altered Ca2+ handling, studying underlying mechanisms and consequences.
Methods and Results— We measured ventricular cardiomyocyte [Ca2+]i (Indo1-AM), L-type Ca2+-current (ICaL) and APs (whole-cell perforated-patch), and Ca2+-handling protein expression (immunoblot). CAVB increased AP duration, cell shortening, systolic [Ca2+]i transients, and caffeine-induced [Ca2+]i release, and CAVB cells showed spontaneous early afterdepolarizations (EADs). ICaL density was unaffected by CAVB, but inactivation was shifted to more positive voltages, increasing the activation-inactivation overlap zone for ICaL window current. Ca2+-calmodulin–dependent protein kinase-II (CaMKII) autophosphorylation was enhanced in CAVB, indicating CaMKII activation. CAVB also enhanced CaMKII-dependent phospholamban-phosphorylation and accelerated [Ca2+]i-transient decay, consistent with phosphorylation-induced reductions in phospholamban inhibition of sarcoplasmic reticulum (SR) Ca2+-ATPase as a contributor to enhanced SR Ca2+ loading. The CaMKII-inhibitor KN93 reversed CAVB-induced changes in caffeine-releasable [Ca2+]i and ICaL inactivation voltage and suppressed CAVB-induced EADs. Similarly, the calmodulin inhibitor W7 suppressed CAVB-induced ICaL inactivation voltage shifts and EADs, and a specific CaMKII inhibitory peptide prevented ICaL inactivation voltage shifts. The SR Ca2+-uptake inhibitor thapsigargin and the SR Ca2+ release inhibitor ryanodine also suppressed CAVB-induced EADs, consistent with an important role for SR Ca2+ loading and release in arrhythmogenesis. AP-duration changes reached a maximum after 1 week of bradypacing, but peak alterations in CaMKII and [Ca2+]i required 2 weeks, paralleling the EAD time course.
Conclusions— CAVB-induced remodeling enhances [Ca2+]i load and activates the Ca2+-calmodulin-CaMKII system, producing [Ca2+]i-handling abnormalities that contribute importantly to CAVB-induced arrhythmogenic afterdepolarizations. |
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R Wakili
,
Y. H Yeh
,
X Yan Qi
,
M Greiser
,
D Chartier
,
K Nishida
,
A Maguy
,
L. R Villeneuve
,
P Boknik
,
N Voigt
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J Krysiak
,
S Kaab
,
U Ravens
,
W. A Linke
,
G. J. M Stienen
,
Y Shi
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J. C Tardif
,
U Schotten
,
D Dobrev
and
S. Nattel
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Background—
Atrial fibrillation impairs atrial contractility, inducing atrial stunning that promotes thromboembolic stroke. Action potential (AP)-prolonging drugs are reported to normalize atrial hypocontractility caused by atrial tachycardia remodeling (ATR). Here, we addressed the role of AP duration (APD) changes in ATR-induced hypocontractility.
Methods and Results—
ATR (7-day tachypacing) decreased APD (perforated patch recording) by 50%, atrial contractility (echocardiography, cardiomyocyte video edge detection), and [Ca2+]i transients. ATR AP waveforms suppressed [Ca2+]i transients and cell shortening of control cardiomyocytes; whereas control AP waveforms improved [Ca2+]i transients and cell shortening in ATR cells. However, ATR cardiomyocytes clamped with the same control AP waveform had 60% smaller [Ca2+]i transients and cell shortening than control cells. We therefore sought additional mechanisms of contractile impairment. Whole-cell voltage clamp revealed reduced ICaL; ICaL inhibition superimposed on ATR APs further suppressed [Ca2+]i transients in control cells. Confocal microscopy indicated ATR-impaired propagation of the Ca2+ release signal to the cell center in association with loss of t-tubular structures. Myofilament function studies in skinned permeabilized cardiomyocytes showed altered Ca2+ sensitivity and force redevelopment in ATR, possibly due to hypophosphorylation of myosin-binding protein C and myosin light-chain protein 2a (immunoblot). Hypophosphorylation was related to multiple phosphorylation system abnormalities where protein kinase A regulatory subunits were downregulated, whereas autophosphorylation and expression of Ca2+-calmodulin-dependent protein kinase II and protein phosphatase 1 activity were enhanced. Recovery of [Ca2+]i transients and cell shortening occurred in parallel after ATR cessation.
Conclusions—
Shortening of APD contributes to hypocontractility induced by 1-week ATR but accounts for it only partially. Additional contractility-suppressing mechanisms include ICaL current reduction, impaired subcellular Ca2+ signal transmission, and altered myofilament function associated with abnormal myosin and myosin-associated protein phosphorylation. The complex mechanistic basis of the atrial hypocontractility associated with AF argues for upstream therapeutic targeting rather than interventions directed toward specific downstream pathophysiological derangements.
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