IKr channel blockade to unmask occult congenital long QT syndrome

BackgroundPatients with genetic evidence of long QT syndromes type 1 and 2 (LQT1, associated with impaired outward potassium current IKs; and LQT2, associated with impaired outward potassium current IKr) 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.ObjectiveThe 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 IKr channel blockade would prolong the QT interval excessively in subjects with LQTS compared with controls and that IKr 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.MethodsSubjects with known LQT1 (n = 5) and LQT2 (n = 6) mutations but baseline QTc ≤450 ms and age- and gender-matched controls (n = 22) received intravenous erythromycin (an IKr blocker). RR, QRS, QT, and Tpe intervals were measured at baseline and after drug infusion.ResultsErythromycin caused only modest QT prolongation in all groups. In contrast, Tpe was specifically prolonged by IKr channel blockade in LQT2 subjects but not in LQT1 subjects or controls.ConclusionShort-acting IKr 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 IKr channel blockade supports the repolarization reserve hypothesis.