PMID- 34623182
OWN - NLM
STAT- MEDLINE
DCOM- 20211206
LR  - 20221202
IS  - 1522-1539 (Electronic)
IS  - 0363-6135 (Print)
IS  - 0363-6135 (Linking)
VI  - 321
IP  - 6
DP  - 2021 Dec 1
TI  - Hypernatremia and intercalated disc edema synergistically exacerbate long-QT 
      syndrome type 3 phenotype.
PG  - H1042-H1055
LID - 10.1152/ajpheart.00366.2021 [doi]
AB  - Cardiac voltage-gated sodium channel gain-of-function prolongs repolarization in 
      the long-QT syndrome type 3 (LQT3). Previous studies suggest that narrowing the 
      perinexus within the intercalated disc, leading to rapid sodium depletion, 
      attenuates LQT3-associated action potential duration (APD) prolongation. However, 
      it remains unknown whether extracellular sodium concentration modulates APD 
      prolongation during sodium channel gain-of-function. We hypothesized that 
      elevated extracellular sodium concentration and widened perinexus synergistically 
      prolong APD in LQT3. LQT3 was induced with sea anemone toxin (ATXII) in 
      Langendorff-perfused guinea pig hearts (n = 34). Sodium concentration was 
      increased from 145 to 160 mM. Perinexal expansion was induced with mannitol or 
      the sodium channel beta1-subunit adhesion domain antagonist (betaadp1). Epicardial 
      ventricular action potentials were optically mapped. Individual and combined 
      effects of varying clefts and sodium concentrations were simulated in a 
      computational model. With ATXII, both mannitol and betaadp1 significantly widened 
      the perinexus and prolonged APD, respectively. The elevated sodium concentration 
      alone significantly prolonged APD as well. Importantly, the combination of 
      elevated sodium concentration and perinexal widening synergistically prolonged 
      APD. Computational modeling results were consistent with animal experiments. 
      Concurrently elevating extracellular sodium and increasing intercalated disc 
      edema prolongs repolarization more than the individual interventions alone in 
      LQT3. This synergistic effect suggests an important clinical implication that 
      hypernatremia in the presence of cardiac edema can markedly increase 
      LQT3-associated APD prolongation. Therefore, to our knowledge, this is the first 
      study to provide evidence of a tractable and effective strategy to mitigate LQT3 
      phenotype by means of managing sodium levels and preventing cardiac edema in 
      patients.NEW & NOTEWORTHY This is the first study to demonstrate that the long-QT 
      syndrome type 3 (LQT3) phenotype can be exacerbated or concealed by regulating 
      extracellular sodium concentrations and/or the intercalated disc separation. The 
      animal experiments and computational modeling in the current study reveal a 
      critically important clinical implication: sodium dysregulation in the presence 
      of edema within the intercalated disc can markedly increase the risk of 
      arrhythmia in LQT3. These findings strongly suggest that maintaining 
      extracellular sodium within normal physiological limits may be an effective and 
      inexpensive therapeutic option for patients with congenital or acquired sodium 
      channel gain-of-function diseases.
FAU - Wu, Xiaobo
AU  - Wu X
AUID- ORCID: 0000-0002-3136-5059
AD  - Translational Biology, Medicine, and Health Graduate Program, Virginia 
      Polytechnic Institute and State University, Roanoke, Virginia.
AD  - Center for Heart and Reparative Medicine Research, Fralin Biomedical Research 
      Institute at Virginia Tech Carilion, Roanoke, Virginia.
FAU - Hoeker, Gregory S
AU  - Hoeker GS
AUID- ORCID: 0000-0002-3917-4791
AD  - Center for Heart and Reparative Medicine Research, Fralin Biomedical Research 
      Institute at Virginia Tech Carilion, Roanoke, Virginia.
FAU - Blair, Grace A
AU  - Blair GA
AD  - Translational Biology, Medicine, and Health Graduate Program, Virginia 
      Polytechnic Institute and State University, Roanoke, Virginia.
AD  - Center for Heart and Reparative Medicine Research, Fralin Biomedical Research 
      Institute at Virginia Tech Carilion, Roanoke, Virginia.
FAU - King, D Ryan
AU  - King DR
AUID- ORCID: 0000-0002-6468-6393
AD  - Translational Biology, Medicine, and Health Graduate Program, Virginia 
      Polytechnic Institute and State University, Roanoke, Virginia.
AD  - Center for Heart and Reparative Medicine Research, Fralin Biomedical Research 
      Institute at Virginia Tech Carilion, Roanoke, Virginia.
FAU - Gourdie, Robert G
AU  - Gourdie RG
AD  - Center for Heart and Reparative Medicine Research, Fralin Biomedical Research 
      Institute at Virginia Tech Carilion, Roanoke, Virginia.
AD  - Department of Biomedical Engineering and Mechanics, Virginia Polytechnic 
      Institute and State University, Blacksburg, Virginia.
FAU - Weinberg, Seth H
AU  - Weinberg SH
AUID- ORCID: 0000-0003-1170-0419
AD  - Department of Biomedical Engineering, Davis Heart and Lung Research Institute, 
      The Ohio State University, Columbus, Ohio.
FAU - Poelzing, Steven
AU  - Poelzing S
AUID- ORCID: 0000-0002-6979-1264
AD  - Translational Biology, Medicine, and Health Graduate Program, Virginia 
      Polytechnic Institute and State University, Roanoke, Virginia.
AD  - Center for Heart and Reparative Medicine Research, Fralin Biomedical Research 
      Institute at Virginia Tech Carilion, Roanoke, Virginia.
AD  - Department of Biomedical Engineering and Mechanics, Virginia Polytechnic 
      Institute and State University, Blacksburg, Virginia.
LA  - eng
SI  - figshare/10.6084/m9.figshare.14825058
SI  - figshare/10.6084/m9.figshare.16624240
GR  - F31 HL160172/HL/NHLBI NIH HHS/United States
GR  - R01HL138003/HHS | NIH | National Heart, Lung, and Blood Institute (NHLBI)/
GR  - R01HL102298/HHS | NIH | National Heart, Lung, and Blood Institute (NHLBI)/
GR  - F31HL147438/HHS | NIH | National Heart, Lung, and Blood Institute (NHLBI)/
GR  - R35 HL161237/HL/NHLBI NIH HHS/United States
GR  - R01 HL102298/HL/NHLBI NIH HHS/United States
GR  - R01 HL138003/HL/NHLBI NIH HHS/United States
GR  - R01HL141855/HHS | NIH | National Heart, Lung, and Blood Institute (NHLBI)/
GR  - F31 HL147438/HL/NHLBI NIH HHS/United States
GR  - R01 HL141855/HL/NHLBI NIH HHS/United States
GR  - F31HL160172/HHS | NIH | National Heart, Lung, and Blood Institute (NHLBI)/
GR  - R01 HL056728/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20211008
PL  - United States
TA  - Am J Physiol Heart Circ Physiol
JT  - American journal of physiology. Heart and circulatory physiology
JID - 100901228
RN  - 0 (Cnidarian Venoms)
RN  - 0 (NAV1.5 Voltage-Gated Sodium Channel)
RN  - 60748-45-0 (toxin II (Anemonia sulcata))
RN  - 9NEZ333N27 (Sodium)
RN  - Long Qt Syndrome 3
SB  - IM
MH  - *Action Potentials
MH  - Animals
MH  - Cnidarian Venoms
MH  - Computer Simulation
MH  - Disease Models, Animal
MH  - Edema, Cardiac/*complications/*metabolism/pathology/physiopathology
MH  - Guinea Pigs
MH  - *Heart Rate
MH  - Hypernatremia/*blood/*complications/physiopathology
MH  - Isolated Heart Preparation
MH  - Long QT Syndrome/chemically induced/*metabolism/physiopathology
MH  - Male
MH  - Models, Cardiovascular
MH  - Myocytes, Cardiac/*metabolism/pathology
MH  - NAV1.5 Voltage-Gated Sodium Channel/*metabolism
MH  - Sodium/*blood
PMC - PMC8793943
OTO - NOTNLM
OT  - Nav1.5
OT  - action potential duration
OT  - gain-of-function
OT  - perinexus
OT  - sodium concentration
COIS- No conflicts of interest, financial or otherwise, are declared by the authors.
EDAT- 2021/10/09 06:00
MHDA- 2021/12/15 06:00
PMCR- 2022/12/01
CRDT- 2021/10/08 12:13
PHST- 2021/10/09 06:00 [pubmed]
PHST- 2021/12/15 06:00 [medline]
PHST- 2021/10/08 12:13 [entrez]
PHST- 2022/12/01 00:00 [pmc-release]
AID - H-00366-2021 [pii]
AID - 10.1152/ajpheart.00366.2021 [doi]
PST - ppublish
SO  - Am J Physiol Heart Circ Physiol. 2021 Dec 1;321(6):H1042-H1055. doi: 
      10.1152/ajpheart.00366.2021. Epub 2021 Oct 8.