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Late Na + Current Contributes to Arrhythmogenic Diastolic Ca 2+ release in catecholaminergic polymorphic ventricular tachycardia (CPVT)
Author(s) -
Radwanski Przemyslaw,
Ho HsiangTing,
Knollmann Björn,
Belevych Andriy,
Gyorke Sandor
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.1274.3
Subject(s) - catecholaminergic polymorphic ventricular tachycardia , medicine , calsequestrin , ryanodine receptor , myocyte , ryanodine receptor 2 , immunocytochemistry , cardiology , endoplasmic reticulum , tetrodotoxin , endocrinology , chemistry , calcium , biochemistry
Arrhythmias caused by abnormal impulse formation including CPVT are associated with aberrant diastolic Ca 2+ release (DCR) from the sarcoplasmic reticulum. Despite high response of CPVT to agents directly affecting Ca 2+ cycling, the incidence of refractory cases is still significant. Surprisingly, these patients often respond to treatment with Na + channel blockers. However, the relationship between Na + influx and the arrhythmogenic disturbances in Ca 2+ handling (aberrant Na + /Ca 2+ signaling) in CPVT remains elusive. To address this issue we used a murine model of cardiac calsequestrin‐associated CPVT. We performed confocal microscopy in isolated ventricular myocytes to assess Ca 2+ handling during various pharmacological interventions. Immunocytochemistry experiments were performed to determine the structural underpinnings of Na + /Ca 2+ signaling. Late Na + current (I Na ) was assessed in whole cell patch‐clamp mode. To monitor arrhythmic activity in vivo surface electrocardiograms were performed before and after intraperitoneal injection of epinephrine (1.5mg/kg) and caffeine (120mg/kg). Immunocytochemistry experiments revealed that neuronal Na + channels (nNa v ) colocalize with the ryanodine receptors (RyR2) Ca 2+ release channels on the sarcoplasmic reticulum. Isoproterenol (Iso; 100nM) induced late I Na in isolated CPVT myocytes which was sensitive to 100nM tetrodotoxin (TTX). Furthermore, nNa v blockade with either TTX, riluzole (10μM) or flecainide (2.5 μM) reduced DCR frequency. This antiarrhythmic effect on cellular level translated in decreased ventricular tachycardia (VT) incidence in vivo . On the other hand, nNa v augmentation with β‐Pompilidotoxin (β‐PMTX, 40μM) increased both the late I Na as well as DCR frequency and VT all of which were reversed by nNa v blockade with riluzole or flecainide. These data suggest that Iso‐promoted, nNa v ‐mediated late I Na contributes to the generation of arrhythmogenic DCR in CPVT and can therefore serve as an antiarrhythmic target. Support or Funding Information This work was supported by NIH Grants R01‐HL074045, R01‐HL063043 (to S.G.) and K99‐HL127299 (to P.B.R).