The group of ECGs from the seven TQT studies included 411 healthy individuals. Each individual had triplicate ECGs in all studies but one. A set of 4874 digital ECGs were processed. The description of the study populations is provided in .
Clinical Characteristics of the Study Populations
At the time of study, the total number of individuals in the International Registry in so-called LQT2 families was 622. LQT2 families have at least one individual with a KCNH2 mutation. From these individuals, the registry contained 1674 ECG tracings including 1145 from 301 LQT2 carriers patients and 529 tracings from 321 non-carriers. Digitization of tracings was not feasible in 40.3% of the tracings from LQT2 carriers and 49.3% of ECGs from non-carrier LQT2. We selected the oldest ECGs from each individual. The final numbers of ECGs were 204 and 189 for carrier and non-carrier LQT2, respectively.
The analysis of the ECG using the software COMPAS was feasible on 150 non-carrier LQT2 patients and 143 carrier LTQ2 patients. Amongst the selected ECGs, 61% and 34% were baseline ECGs in the non-carriers and carrier groups, respectively (see ).
Schematic description of the processes involved in the digitization of the paper ECG tracings from LQT2 families.
In LQT2 carriers, cardiac events (CE) were defined as cardiac arrest, syncope, or sudden cardiac death. We identified 69 LQT2 carrier patients with CE. Because of the small number of cases in this group, we did not use learning and validation dataset.
Profiling T-wave morphology in acquired and inherited LQT2
The RR values were similarly distributed between healthy individuals on and off moxifloxacin. They were significantly higher (976±149msec) in LQT2 carrier in comparison to their non-affected relatives (875±145msec, p<0.001). The QTc intervals were not different between healthy and non-carrier individuals (411±23 vs. 405±29 msec) but ECGs of individuals on moxifloxacin were associated with significant QTc prolongation of ~12 msec (422±26msec, p<0.001) in comparison to these two groups. As expected, LQT2 carriers present ECGs with longer QTc interval duration (470±47msec, p<0.001) in comparison to non-affected family members (405±29msec).
An increased TpTe interval (105±35 vs. 75±13msec, p<0.001), lower T-wave amplitude (0.18±0.10 vs. 0.27±0.12mV, p<0.001) and flatter right (2.4±1.6 vs. 4.5±2.2μV/msec, p<0.001) i
and left slopes (1.7±1.1 vs. 3.3±1.5μV/msec, p<0.001) of T-wave characterize the T-wave of LQT2 patients. The vectorial parameters confirmed an increased T-loop roundness (0.43±0.19 vs. 0.33±0.17, p<0.001) in patients with a mutation. The ERDs and LRDs parameters were all increased in averaged by 45% in carrier LQT2 patients (in comparison to 16 % for the QTc interval), these differences were all significant with a p value inferior to 0.001.
From ECGs of healthy individuals on and off moxifloxacin, we observed a very subtle effect on the morphology of the T-wave. The QTc, QTac and TpTe interval were prolonged in average by 12, 7 and 4 msec respectively (p<0.001). The T-wave right and left slopes very slightly decreased in absolute value of 0.5 and 0.2μV/msec (p<0.005). However, the T-wave amplitude and T-roundness did not reveal any significant change. The ERDs and LRDs captured a small repolarization delay (<5msec) with statistical significance (p<0.001): ERD30% was 40±8 vs. 44±9msec, ERD50% was 66±15 vs. 71±16 msec, LRD30% was 28±5 vs. 30±6 msec and ERD50% was 41±7 vs. 44±8msec.
reports the values of the investigated ECG parameters between the groups of LQT2 carrier patients with (N=74) and without CE (N=69). Significant different values between LQT2 patients with and without events were observed: QTc (477±44 vs. 462±50msec, p=0.026), QTac (373±42 vs. 354±40msec, p=0.013), αL from ev1 (4.1±2.8 vs. 5.0±2.7μV/msec, p=0.008), T amplitude (0.51±0.30 vs. 0.62±0.29mV, p=0.003) and T roundness (0.47±0.19 vs. 0.39±0.18msec, p=0.006).
ECG measurements in LQT2 patients with and without cardiac events
Investigating complementarities between abnormal T-wave morphology and QT/QTc prolongation in acquired and inherited LQT2
In , we report the best multivariate models and associated odds ratios when designed on the learning set and when applied to the validation datasets for the moxi. model () and for the LQTS model (). In , we provide the Cox models for CE in LQT2 carriers.
a: Summary of the “moxifloxacin models” and associated odds ratios in the validation sets.
We used two different heart rate formula for QTc: Bazett’s (QTcB) and Fridericia’s (QTcF). The RR values did not contribute to the moxi model when QTcF was forced in; however RR did contribute if we forced QTcB instead of QTcF. These results confirmed that Fridericia’s formula satisfactorily corrects QT for heart rate but Bazett’s does not.8
In the LQTS model, Bazett’s formula was found to correct better than Fridericia’s confirming specific impairment of QT and RR profiles in LQT2.
We investigated if scalar T-wave morphological parameters (from lead II) would bring additional information to QT/QTc and RR intervals to detect the presence of Ikr blockade. In the moxi model, none of the scalar parameters contributed significantly to the models. While in the LQTS model the left tangent of the T-wave (from lead II) was associated with a significant odds ratio (0.38, 95% confidence interval [CI]: 0.23-0.64, p=0.0002) corresponding to a 62% increase probability of being carrier for each 1.5 μV/ms decrease in the right slope of the T-wave.
T-wave morphology measured from eigenleads significantly contributed in both the moxi. and the LQTS models. In the moxi model, ERD30% was selected as the parameter contributing the most with 12% increase probability of being on moxifloxacin for each millisecond increases in ERD30% (OR:1.12, CI: 1.09-1.30, p<0.0001). The validation of this model on the independent set of data confirmed the importance of ERD30% with a 15% increase probability per same increment (OR=1.15, CI: 1.04-1.26, p<0.0001). For the LQT2 groups, as it was found in the scalar model the left slope (αL) was selected but the measurement from lead ev1 did performed better than from lead II. Results were similar between the learning and validation sets ~60% increased probability of carrying a KCNH2 mutation for each 1.5 μV/ms decrease in slope (OR=0.46, CI: 0.28-0.75, p=0.002 in the learning set and OR=0.38, CI: 0.23-0.64, p=0.0002 in the validation set). Then, we evaluated the same model on all LQT2 carriers and non-carriers with QTc <500msec and QTc <470msec. In both subgroups, the same model remained valid. The OR for QTc decreased from 3.17 to 2.90 (p<0.0001) for the groups with QTc<500msec (N=263) and QTc <470msec (N=211), respectively (while OR values for αL was similar 0.32 and 0.35, p<0.0001). In , we plotted on the left panel the receiver operating characteristics (ROC) curves for discriminating between LQT2 carriers and non-carriers for all the study population, and on the right panel for the patients with normal QTc. The ROC curves emphasize the benefit associated with the morphological factors when investigating the most clinically challenging patients i.e. the LQTS patient carriers with normal QTc interval duration.
Figure 3 Receiver operating characteristic curves for the discrimination of carriers from non-carrier LQT2 patients using 3 logistic models. The left panel shows the limited benefit of considering αL in addition to RR and QTc in LQT2 patients with prolong (more ...)
The CE model revealed that 1-msec increased in QTc duration was significantly associated with CE in LQT2 (HR=1.01, CI: 1.00-1.01, p=0.045), and increased T-roundness was associated with significant HR as well. A 15% increased probability of CE in LQTS patients for each 10% increase in roundness. After adjustment for presence of beta-blocker therapy, the results were not changed, HR for T-roundness was 1.15 (CI: 1.01-1.31, p=0.036). provides the Kaplan-Meier survival curves for T-roundness superior and inferior to its third quartile for all population (), for the subgroup of patients with QTc≥500msec (N=25, ), and for patients with QTc <500msec (N=115, ). The survival curves show significantly higher probability for CE in patients with an increased T-roundness for the overall population and for a population including patients with QTc<500 msec only. T-roundness was not found useful in LQTS patients clinically identifiable i.e. with a QTc≥500msec.
Kaplan-Meier curves describing the probability of cardiac events in LQT2 patients based on T roundness. Panel A: all population; panel B: LQT2 carriers with QTc≥500 msec and panel C: LQT2 carriers with QTc<500msec