PMID- 30654134
OWN - NLM
STAT- MEDLINE
DCOM- 20201104
LR  - 20240607
IS  - 1556-3871 (Electronic)
IS  - 1547-5271 (Print)
IS  - 1547-5271 (Linking)
VI  - 16
IP  - 7
DP  - 2019 Jul
TI  - Calcium/calmodulin-dependent protein kinase II causes atrial structural 
      remodeling associated with atrial fibrillation and heart failure.
PG  - 1080-1088
LID - S1547-5271(19)30013-X [pii]
LID - 10.1016/j.hrthm.2019.01.013 [doi]
AB  - BACKGROUND: Atrial fibrillation (AF) is sustained by reentrant mechanisms that 
      depend, in part, on atrial structural remodeling. Increased 
      Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) activity occurs in 
      persistent AF. A general consensus has been that electrophysiological actions of 
      CaMKII must be the contributing factor, but electrical remodeling in AF differs 
      considerably with electrophysiological effects of CaMKII. CaMKII has been 
      associated with structural remodeling in several tissues, but not the cardiac 
      atria. The role of CaMKII in sustaining AF remains undefined. OBJECTIVE: The 
      purpose of this study was to assess the effects of CaMKII on AF-related 
      structural remodeling. METHODS: We evaluated the objective in a porcine AF-heart 
      failure model using atrial gene transfer of the CaMKII inhibitory peptide 
      CaMKIIn. We used conventional methods including in vivo electrophysiological 
      study, telemetry, western blot, echocardiography, and histology to quantify 
      rhythm, function, microstructure, and signaling pathways relevant to CaMKII and 
      structural remodeling. RESULTS: CaMKII levels and activity increased 
      progressively in the early stages of AF-heart failure. Inhibiting CaMKII 
      preserved atrial contractile function and attenuated atrial hypertrophy, 
      fibrosis, and apoptosis but did not affect inflammation or myolysis. These 
      effects were accompanied by significantly decreased phosphorylation of HDAC4, 
      decreased expression of p38MAP-kinase, and alterations in the phosphorylation 
      pattern and relative ratios of JNK isoforms. CONCLUSION: Our findings suggest 
      that CaMKII mediates signaling pathways related to atrial contractile function 
      and structural remodeling in AF. CaMKII inhibition is potentially a novel therapy 
      for AF. These findings are of importance because no clinically relevant mediators 
      of either atrial contractile function or structural remodeling have yet been 
      identified.
CI  - Copyright (c) 2019 Heart Rhythm Society. Published by Elsevier Inc. All rights 
      reserved.
FAU - Liu, Zhao
AU  - Liu Z
AD  - Division of Cardiology, University of Massachusetts Medical School, Worcester, 
      Massachusetts.
FAU - Finet, J Emanuel
AU  - Finet JE
AD  - Division of Cardiology, Cleveland Clinic Foundation, Cleveland, Ohio.
FAU - Wolfram, Julie A
AU  - Wolfram JA
AD  - Division of Cardiology, University of Massachusetts Medical School, Worcester, 
      Massachusetts.
FAU - Anderson, Mark E
AU  - Anderson ME
AD  - Department of Medicine, Johns Hopkins University Medical School, Baltimore, 
      Maryland.
FAU - Ai, Xun
AU  - Ai X
AD  - Department of Physiology & Biophysics, Rush University Medical School, Chicago, 
      Illinois.
FAU - Donahue, J Kevin
AU  - Donahue JK
AD  - Division of Cardiology, University of Massachusetts Medical School, Worcester, 
      Massachusetts. Electronic address: donahuelab@gmail.com.
LA  - eng
GR  - R01 HL079031/HL/NHLBI NIH HHS/United States
GR  - R01 HL096652/HL/NHLBI NIH HHS/United States
GR  - R01 HL093486/HL/NHLBI NIH HHS/United States
GR  - R01 HL070250/HL/NHLBI NIH HHS/United States
GR  - R35 HL140034/HL/NHLBI NIH HHS/United States
GR  - R01 HL168728/HL/NHLBI NIH HHS/United States
GR  - R01 HL113640/HL/NHLBI NIH HHS/United States
GR  - R01 HL113001/HL/NHLBI NIH HHS/United States
GR  - R01 HL130376/HL/NHLBI NIH HHS/United States
GR  - R01 AA024769/AA/NIAAA NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20190114
PL  - United States
TA  - Heart Rhythm
JT  - Heart rhythm
JID - 101200317
RN  - EC 2.7.11.17 (Calcium-Calmodulin-Dependent Protein Kinase Type 2)
SB  - IM
CIN - Heart Rhythm. 2019 Jul;16(7):1089-1090. doi: 10.1016/j.hrthm.2019.02.002. PMID: 
      30735791
MH  - Animals
MH  - *Atrial Fibrillation/enzymology/physiopathology
MH  - *Atrial Remodeling
MH  - *Calcium-Calmodulin-Dependent Protein Kinase Type 2/physiology
MH  - Disease Models, Animal
MH  - Electrocardiography
MH  - *Heart Failure/enzymology/physiopathology
MH  - Signal Transduction
MH  - Swine
MH  - Telemetry
PMC - PMC6800146
MID - NIHMS1015864
OTO - NOTNLM
OT  - Apoptosis
OT  - Atrial fibrillation
OT  - Ca/calmodulin-dependent protein kinase
OT  - Fibrosis
OT  - Gene therapy
COIS- The remaining authors report no conflicts relevant to the contents of this paper 
      to disclose.
EDAT- 2019/01/18 06:00
MHDA- 2020/11/04 06:00
PMCR- 2019/10/18
CRDT- 2019/01/18 06:00
PHST- 2018/06/21 00:00 [received]
PHST- 2019/01/18 06:00 [pubmed]
PHST- 2020/11/04 06:00 [medline]
PHST- 2019/01/18 06:00 [entrez]
PHST- 2019/10/18 00:00 [pmc-release]
AID - S1547-5271(19)30013-X [pii]
AID - 10.1016/j.hrthm.2019.01.013 [doi]
PST - ppublish
SO  - Heart Rhythm. 2019 Jul;16(7):1080-1088. doi: 10.1016/j.hrthm.2019.01.013. Epub 
      2019 Jan 14.