I(Kr) channel blockade to unmask occult congenital long QT syndrome.
BACKGROUND
Patients with genetic evidence of long QT syndromes type 1 and 2 (LQT1, associated with impaired outward potassium current I(Ks); and LQT2, associated with impaired outward potassium current I(Kr)) may have normal baseline QT intervals (phenotype/genotype discordance) and elude clinical detection. Beta-adrenergic stimulation may unmask occult LQT1, but no maneuver has consistently unmasked the LQT2 phenotype.


OBJECTIVE
The purpose of this study was to test the repolarization reserve hypothesis (multiple challenges to repolarization are required to produce an abnormal phenotype), using subjects with LQT1 and LQT2 mutations but normal QT interval. We hypothesized that I(Kr) channel blockade would prolong the QT interval excessively in subjects with LQTS compared with controls and that I(Kr) channel blockade could unmask the abnormal LQTS phenotype in subjects with LQTS versus controls, as measured by the T peak-to-end interval (Tpe), a sensitive measure of abnormal repolarization.


METHODS
Subjects with known LQT1 (n = 5) and LQT2 (n = 6) mutations but baseline QTc < or = 450 ms and age- and gender-matched controls (n = 22) received intravenous erythromycin (an I(Kr) blocker). RR, QRS, QT, and Tpe intervals were measured at baseline and after drug infusion.


RESULTS
Erythromycin caused only modest QT prolongation in all groups. In contrast, Tpe was specifically prolonged by I(Kr) channel blockade in LQT2 subjects but not in LQT1 subjects or controls.


CONCLUSIONS
Short-acting I(Kr) channel blockade, together with the sensitive repolarization measure Tpe, can unmask abnormal repolarization in LQT2. Our finding of abnormal repolarization in LQT2 subjects exposed to I(Kr) channel blockade supports the repolarization reserve hypothesis.
Jeyaraj
Darwin
D
Heart and Vascular Research Center, MetroHealth Campus of Case Western Reserve University, Cleveland, Ohio 44109-1998, USA.
Abernethy
Denise P
DP
Natarajan
Rupa N
RN
Dettmer
Mary M
MM
Dikshteyn
Maria
M
Meredith
Diana M
DM
Patel
Kevin
K
Allareddy
Raghavendra R
RR
Lewis
Steven A
SA
Kaufman
Elizabeth S
ES
D000319:Adrenergic beta-Antagonists / Q000494:pharmacology*; D000328:Adult; D016022:Case-Control Studies; D004917:Erythromycin / Q000008:administration & dosage / Q000494:pharmacology*; D005260:Female; D006801:Humans; D008133:Long QT Syndrome / Q000235:genetics / Q000503:physiopathology*; D008297:Male; D009154:Mutation; D010641:Phenotype; D026902:Potassium Channel Blockers / Q000627:therapeutic use*; D015221:Potassium Channels / Q000187:drug effects*; D011433:Propranolol / Q000494:pharmacology*
D000319:Adrenergic beta-Antagonists; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D004917:Erythromycin; D011433:Propranolol