T wave morphology analysis distinguishes between KvLQT1 and HERG mutations in long QT syndrome

OBJECTIVES The aim of this study was to develop an objective method to distinguish between HERG and KvLQT1 genotypes on the surface ECG. BACKGROUND The two most prevalent genes affected in long QT syndrome (LQTS) are KvLQT1 (KCNQ1) and HERG (KCNH2), which are mutated in >90% of patients with a reported LQTS genotype. It is known that T waves have lower amplitude and more notches in HERG patients than T waves in KvLQT1 patients, but this semiquantitative method lacks the discriminative power to be used in a clinical setting. We developed a simple mathematical method that allowed us to quantify T wave shape in LQTS mutations for clinical use. METHODS ECGs from 24 HERG patients, 13 KvLQT1 LQTS patients, and 13 healthy relatives were examined. The repolarizing integral (RI) was constructed from the T wave. The resulting RI is sigmoid and was modeled using the Hill equation as (RI(t) = V-max*[t(n)/[K-m(n) + t(n)]]). V-max is equivalent to the total T wave area, K-m is the time when 50% of the T wave area is reached, and n is a measure of the slope of the sigmoid RI. RESULTS The RI correlated nearly perfectly to the fitted sigmoid, r = 0.99. In lead V-2, V-max was larger in KvLQT1 (0.148 +/- 0.021) (mean +/- SE) compared to HERG (0.080 +/- 0.012) and controls (0.067 +/- 0.021). The Hill coefficient n of the RI discriminated perfectly between HERG (2.00 +/- 0.11) and KvLQT1 (4.11 +/- 0.15). CONCLUSIONS RI allows distinguishing between HERG and KvLQT1 mutations based solely on the T wave morphology in the present LQTS population.