PMID- 10532948
OWN - NLM
STAT- MEDLINE
DCOM- 19991116
LR  - 20190706
IS  - 1524-4571 (Electronic)
IS  - 0009-7330 (Linking)
VI  - 85
IP  - 9
DP  - 1999 Oct 29
TI  - Ionic mechanisms responsible for the electrocardiographic phenotype of the
      Brugada syndrome are temperature dependent.
PG  - 803-9
AB  - The Brugada syndrome is a major cause of sudden death, particularly among young
      men of Southeast Asian and Japanese origin. The syndrome is characterized
      electrocardiographically by an ST-segment elevation in V1 through V3 and a rapid 
      polymorphic ventricular tachycardia that can degenerate into ventricular
      fibrillation. Our group recently linked the disease to mutations in SCN5A, the
      gene encoding for the alpha subunit of the cardiac sodium channel. When
      heterologously expressed in frog oocytes, electrophysiological data recorded from
      the Thr1620Met missense mutant failed to adequately explain the
      electrocardiographic phenotype. Therefore, we sought to further characterize the 
      electrophysiology of this mutant. We hypothesized that at more physiological
      temperatures, the missense mutation may change the gating of the sodium channel
      such that the net outward current is dramatically augmented during the early
      phases of the right ventricular action potential. In the present study, we test
      this hypothesis by expressing Thr1620Met in a mammalian cell line, using the
      patch-clamp technique to study the currents at 32 degrees C. Our results indicate
      that Thr1620Met current decay kinetics are faster when compared with the wild
      type at 32 degrees C. Recovery from inactivation was slower for Thr1620Met at 32 
      degrees C, and steady-state activation was significantly shifted. Our findings
      explain the features of the ECG of Brugada patients, illustrate for the first
      time a cardiac sodium channel mutation of which the arrhythmogenicity is revealed
      only at temperatures approaching the physiological range, and suggest that some
      patients may be more at risk during febrile states.
FAU - Dumaine, R
AU  - Dumaine R
AD  - Departments of Molecular Biology and Experimental Cardiology, Masonic Medical
      Research Laboratory, Utica, NY 13501, USA. rdumaine@mmrl.edu
FAU - Towbin, J A
AU  - Towbin JA
FAU - Brugada, P
AU  - Brugada P
FAU - Vatta, M
AU  - Vatta M
FAU - Nesterenko, D V
AU  - Nesterenko DV
FAU - Nesterenko, V V
AU  - Nesterenko VV
FAU - Brugada, J
AU  - Brugada J
FAU - Brugada, R
AU  - Brugada R
FAU - Antzelevitch, C
AU  - Antzelevitch C
LA  - eng
GR  - HL-47678/HL/NHLBI NIH HHS/United States
GR  - HL-59449/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - Circ Res
JT  - Circulation research
JID - 0047103
RN  - 0 (NAV1.5 Voltage-Gated Sodium Channel)
RN  - 0 (SCN5A protein, human)
RN  - 0 (Sodium Channels)
SB  - IM
CIN - Circ Res. 1999 Oct 29;85(9):872-4. PMID: 10532957
MH  - Adult
MH  - Animals
MH  - Bundle-Branch Block/genetics/*physiopathology
MH  - Heart/*physiopathology
MH  - Humans
MH  - Male
MH  - Mutation, Missense/physiology
MH  - NAV1.5 Voltage-Gated Sodium Channel
MH  - Patch-Clamp Techniques
MH  - Sodium Channels/*physiology
MH  - Temperature
MH  - Ventricular Fibrillation/genetics/*physiopathology
EDAT- 1999/10/26 00:00
MHDA- 1999/10/26 00:01
CRDT- 1999/10/26 00:00
PHST- 1999/10/26 00:00 [pubmed]
PHST- 1999/10/26 00:01 [medline]
PHST- 1999/10/26 00:00 [entrez]
AID - 10.1161/01.res.85.9.803 [doi]
PST - ppublish
SO  - Circ Res. 1999 Oct 29;85(9):803-9. doi: 10.1161/01.res.85.9.803.