IKr 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 etude 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 LOTS compared with controls and that I-Kr channel blockade could unmask the abnormal LOTS phenotype in subjects with LOTS 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 <= 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. CONCLUSION 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.