Multiple potential molecular contributors to atrial hypocontractility caused by atrial tachycardia remodeling in dogs.
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.


RESULTS
ATR (7-day tachypacing) decreased APD (perforated patch recording) by ≈50%, atrial contractility (echocardiography, cardiomyocyte video edge detection), and [Ca(2+)](i) transients. ATR AP waveforms suppressed [Ca(2+)](i) transients and cell shortening of control cardiomyocytes; whereas control AP waveforms improved [Ca(2+)](i) transients and cell shortening in ATR cells. However, ATR cardiomyocytes clamped with the same control AP waveform had ≈60% smaller [Ca(2+)](i) transients and cell shortening than control cells. We therefore sought additional mechanisms of contractile impairment. Whole-cell voltage clamp revealed reduced I(CaL); I(CaL) inhibition superimposed on ATR APs further suppressed [Ca(2+)](i) transients in control cells. Confocal microscopy indicated ATR-impaired propagation of the Ca(2+) release signal to the cell center in association with loss of t-tubular structures. Myofilament function studies in skinned permeabilized cardiomyocytes showed altered Ca(2+) 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 Ca(2+)-calmodulin-dependent protein kinase IIδ and protein phosphatase 1 activity were enhanced. Recovery of [Ca(2+)](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 I(CaL) current reduction, impaired subcellular Ca(2+) 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.
Wakili
Reza
R
Department of Medicine and Research Center, Université de Montréal, Montreal, Quebec, Canada.
Yeh
Yung-Hsin
YH
Yan Qi
Xiao
X
Greiser
Maura
M
Chartier
Denis
D
Nishida
Kunihiro
K
Maguy
Ange
A
Villeneuve
Louis-Robert
LR
Boknik
Peter
P
Voigt
Niels
N
Krysiak
Judith
J
Kääb
Stefan
S
Ravens
Ursula
U
Linke
Wolfgang A
WA
Stienen
Gerrit J M
GJ
Shi
Yanfen
Y
Tardif
Jean-Claude
JC
Schotten
Ulrich
U
Dobrev
Dobromir
D
Nattel
Stanley
S
D000200:Action Potentials; D000818:Animals; D001281:Atrial Fibrillation / Q000378:metabolism* / Q000503:physiopathology; D016275:Atrial Function / Q000502:physiology*; D002118:Calcium / Q000378:metabolism*; D004195:Disease Models, Animal; D004285:Dogs; D006325:Heart Atria / Q000503:physiopathology*; D009200:Myocardial Contraction / Q000502:physiology*; D032383:Myocytes, Cardiac / Q000378:metabolism*
D002118:Calcium