title: Multiple potential molecular contributors to atrial hypocontractility caused by atrial tachycardia remodeling in dogs.
abstract: 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.
authors.affiliation: Department of Medicine and Research Center, Université de Montréal, Montreal, Quebec, Canada.
authors.forename: Reza
authors.initials: R
authors.lastname: Wakili
authors.forename: Yung-Hsin
authors.initials: YH
authors.lastname: Yeh
authors.forename: Xiao
authors.initials: X
authors.lastname: Yan Qi
authors.forename: Maura
authors.initials: M
authors.lastname: Greiser
authors.forename: Denis
authors.initials: D
authors.lastname: Chartier
authors.forename: Kunihiro
authors.initials: K
authors.lastname: Nishida
authors.forename: Ange
authors.initials: A
authors.lastname: Maguy
authors.forename: Louis-Robert
authors.initials: LR
authors.lastname: Villeneuve
authors.forename: Peter
authors.initials: P
authors.lastname: Boknik
authors.forename: Niels
authors.initials: N
authors.lastname: Voigt
authors.forename: Judith
authors.initials: J
authors.lastname: Krysiak
authors.forename: Stefan
authors.initials: S
authors.lastname: Kääb
authors.forename: Ursula
authors.initials: U
authors.lastname: Ravens
authors.forename: Wolfgang A
authors.initials: WA
authors.lastname: Linke
authors.forename: Gerrit J M
authors.initials: GJ
authors.lastname: Stienen
authors.forename: Yanfen
authors.initials: Y
authors.lastname: Shi
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Tardif
authors.forename: Ulrich
authors.initials: U
authors.lastname: Schotten
authors.forename: Dobromir
authors.initials: D
authors.lastname: Dobrev
authors.forename: Stanley
authors.initials: S
authors.lastname: Nattel
mesh_terms: 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*
chemical_list: D002118:Calcium