Interventricular differences in sodium current and its potential role in Brugada syndrome

TY - JOUR

T1 - Interventricular differences in sodium current and its potential role in Brugada syndrome

AU - Calloe, Kirstine

AU - Aistrup, Gary L.

AU - Di Diego, José M.

AU - Goodrow, Robert J.

AU - Treat, Jacqueline A.

AU - Cordeiro, Jonathan M.

PY - 2018

Y1 - 2018

N2 - Brugada syndrome (BrS) is an inherited disease associated with ST elevation in the right precordial leads, polymorphic ventricular tachycardia (PVT), and sudden cardiac death in adults. Mutations in the cardiac sodium channel account for a large fraction of BrS cases. BrS manifests in the right ventricle (RV), which led us to examine the biophysical and molecular properties of sodium channel in myocytes isolated from the left (LV) and right ventricle. Patch clamp was used to record sodium current (INa) in single canine RV and LV epicardial (epi) and endocardial (endo) myocytes. Action potentials were recorded from multicellular preparations and single cells. mRNA and proteins were determined using quantitative RT-PCR and Western blot. Although LV wedge preparations were thicker than RV wedges, transmural ECG recordings showed no difference in the width of the QRS complex or transmural conduction time. Action potential characteristics showed RV epi and endo had a lower Vmax compared with LV epi and endo cells. Peak INa density was significantly lower in epi and endo RV cells compared with epi and endo LV cells. Recovery from inactivation of INa in RV cells was slightly faster and half maximal steady-state inactivation was more positive. β2 and β4 mRNA was detected at very low levels in both ventricles, which was confirmed at the protein level. Our observations demonstrate that Vmax and Na+ current are smaller in RV, presumably due to differential Nav1.5/β subunit expression. These results provide a potential mechanism for the right ventricular manifestation of BrS.

AB - Brugada syndrome (BrS) is an inherited disease associated with ST elevation in the right precordial leads, polymorphic ventricular tachycardia (PVT), and sudden cardiac death in adults. Mutations in the cardiac sodium channel account for a large fraction of BrS cases. BrS manifests in the right ventricle (RV), which led us to examine the biophysical and molecular properties of sodium channel in myocytes isolated from the left (LV) and right ventricle. Patch clamp was used to record sodium current (INa) in single canine RV and LV epicardial (epi) and endocardial (endo) myocytes. Action potentials were recorded from multicellular preparations and single cells. mRNA and proteins were determined using quantitative RT-PCR and Western blot. Although LV wedge preparations were thicker than RV wedges, transmural ECG recordings showed no difference in the width of the QRS complex or transmural conduction time. Action potential characteristics showed RV epi and endo had a lower Vmax compared with LV epi and endo cells. Peak INa density was significantly lower in epi and endo RV cells compared with epi and endo LV cells. Recovery from inactivation of INa in RV cells was slightly faster and half maximal steady-state inactivation was more positive. β2 and β4 mRNA was detected at very low levels in both ventricles, which was confirmed at the protein level. Our observations demonstrate that Vmax and Na+ current are smaller in RV, presumably due to differential Nav1.5/β subunit expression. These results provide a potential mechanism for the right ventricular manifestation of BrS.

KW - Action Potentials

KW - left ventricle

KW - patch clamp

KW - right ventricle

KW - sodium current

U2 - 10.14814/phy2.13787

DO - 10.14814/phy2.13787

M3 - Journal article

C2 - 30009404

AN - SCOPUS:85050824398

SN - 2051-817X

VL - 6

JO - Physiological Reports

JF - Physiological Reports

IS - 14

M1 - e13787

ER -