PMID- 28220073
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20220330
IS  - 1663-9812 (Print)
IS  - 1663-9812 (Electronic)
IS  - 1663-9812 (Linking)
VI  - 8
DP  - 2017
TI  - Enhanced Late Na and Ca Currents as Effective Antiarrhythmic Drug Targets.
PG  - 36
LID - 10.3389/fphar.2017.00036 [doi]
LID - 36
AB  - While recent advances clarified the molecular and cellular modes of action of 
      antiarrhythmic drugs (AADs), their link to suppression of dynamical arrhythmia 
      mechanisms remains only partially understood. The current classifications of AADs 
      (Classes I, III, and IV) rely on blocking peak Na, K and L-type calcium currents 
      (I(Ca,L)), with Class II with dominant beta receptor blocking activity and Class 
      V including drugs with diverse classes of actions. The discovery that the calcium 
      and redox sensor, cardiac Ca/calmodulin-dependent protein kinase II (CaMKII) 
      enhances both the late Na (I(Na-L)) and the late I(Ca,L) in patients at high risk 
      of VT/VF provided a new and a rational AAD target. Pathological rise of either or 
      both of I(Na-L) and late I(Ca,L) are demonstrated to promote cellular early 
      afterdepolarizations (EADs) and EAD-mediated triggered activity that can initiate 
      VT/VF in remodeled hearts. Selective inhibition of the I(Na-L) without affecting 
      their peak transients with the highly specific prototype drug, GS-967 suppresses 
      these EAD-mediated VT/VFs. As in the case of I(Na-L), selective inhibition of the 
      late I(Ca,L) without affecting its peak with the prototype drug, roscovitine 
      suppressed oxidative EAD-mediated VT/VF. These findings indicate that specific 
      blockers of the late inward currents without affecting their peaks (gating 
      modifiers), offer a new and effective AAD class action i.e., "Class VI." The 
      development of safe drugs with selective Class VI actions provides a rational and 
      effective approach to treat VT/VF particularly in cardiac conditions associated 
      with enhanced CaMKII activity such as heart failure.
FAU - Karagueuzian, Hrayr S
AU  - Karagueuzian HS
AD  - Translational Arrhythmia Section, David Geffen School of Medicine, University of 
      California, Los AngelesLos Angeles, CA, USA; Cardiovascular Research Laboratory, 
      Departments of Medicine (Cardiology), David Geffen School of Medicine, University 
      of California, Los AngelesLos Angeles, CA, USA.
FAU - Pezhouman, Arash
AU  - Pezhouman A
AD  - Translational Arrhythmia Section, David Geffen School of Medicine, University of 
      California, Los AngelesLos Angeles, CA, USA; Cardiovascular Research Laboratory, 
      Departments of Medicine (Cardiology), David Geffen School of Medicine, University 
      of California, Los AngelesLos Angeles, CA, USA.
FAU - Angelini, Marina
AU  - Angelini M
AD  - Department of Anesthesiology and Perioperative Medicine, David Geffen School of 
      Medicine, University of California, Los Angeles Los Angeles, CA, USA.
FAU - Olcese, Riccardo
AU  - Olcese R
AD  - Cardiovascular Research Laboratory, Departments of Medicine (Cardiology), David 
      Geffen School of Medicine, University of California, Los AngelesLos Angeles, CA, 
      USA; Department of Anesthesiology and Perioperative Medicine, David Geffen School 
      of Medicine, University of California, Los AngelesLos Angeles, CA, USA; 
      Department of Physiology, David Geffen School of Medicine, University of 
      California, Los AngelesLos Angeles, CA, USA.
LA  - eng
GR  - P01 HL078931/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Review
DEP - 20170206
PL  - Switzerland
TA  - Front Pharmacol
JT  - Frontiers in pharmacology
JID - 101548923
PMC - PMC5292429
OTO - NOTNLM
OT  - GS-458-967
OT  - antiarrhythmic drugs
OT  - early afterdepolarization
OT  - late Ca current
OT  - late Na current
OT  - roscovitine
OT  - triggered activity
OT  - ventricular fibrillation
EDAT- 2017/02/22 06:00
MHDA- 2017/02/22 06:01
PMCR- 2017/02/06
CRDT- 2017/02/22 06:00
PHST- 2016/11/14 00:00 [received]
PHST- 2017/01/18 00:00 [accepted]
PHST- 2017/02/22 06:00 [entrez]
PHST- 2017/02/22 06:00 [pubmed]
PHST- 2017/02/22 06:01 [medline]
PHST- 2017/02/06 00:00 [pmc-release]
AID - 10.3389/fphar.2017.00036 [doi]
PST - epublish
SO  - Front Pharmacol. 2017 Feb 6;8:36. doi: 10.3389/fphar.2017.00036. eCollection 
      2017.