Validation Studies

Congential Long QT Syndrome (LQTS)

Drug induced QT prolongation studies conducted by the University of Rochester HRFUP

TdP, T-wave morphology and repolarization instability

Congential LQTS

iCardiac has acquired experience in the analysis of the ventricular repolarization signal from surface ECGs based on the research activity at the University of Rochester Heart Research Follow-Up Program which has been directed toward digital quantitative electrocardiography of the congenital LQTS during the past 10 years. The earliest preliminary investigations were led by Dr. A.J. Moss, initiator of the International Registry for the Congenital LQTS. In a very early investigation of T-wave morphology in various types of the LQTS, Moss et al. reported that the heart-rate corrected QT onset was unusually prolonged in individuals with mutations involving the LQT3 mutation, T amplitude was generally small in LQT2, and T duration was particularly long in lead II of LQT1 patients. Because the various types of congenital LQTS are associated with different ion dysfunctions of the myocardial cells, , , this work suggested that specific T-wave morphologies are associated with specific ion abnormalities. Since the patients with different types of LQTS mutation require different therapeutic strategies, the T-wave morphology was further investigated in the two most common forms of the congenital LQTS: LQT1 (KCNQ1) vs. LQT2 (KCNH2) mutations. The objective was to assess the effectiveness of using widely available and inexpensive ECG technology for identifying the type of LQTS patients instead of lengthy and costly genotyping techniques. The study population consisted of 49 LQT1 and 25 LQT2 carriers from 26 LQT1 families and 19 LQT2 families in whom a 12-lead digital ECG Holter was recorded. The KCNH2 and KCNQ1 mutations were identified using standard genetic tests. Thirty-eight unrelated healthy subjects were included and used as a reference group. As previously described, LQT2 carriers usually present low amplitude (magnitude) of T-waves , lower in comparison to LQT1 carriers and healthy controls. In this study, these results were further confirmed by the observed different values between the groups of T-wave slopes. Right and left slopes of T-wave were significantly lower in LQT2 than LQT1 patients: 8.0 ± 3.0 vs. 3.6 ± 1.7 mV/ms for left slope (p< 0.001) and -12.7 ± 5.1 vs. -4.3 ± 2.6 mV/ms for right slope (p < 0.001). Using a multi-parametric approach based on both QT interval and morphological information, the researchers at the University of Rochester were able to identify correctly 89% of healthy, 84% of LQT1 carriers, and 92% of LQT2 carriers. This study suggested that a quantitative assessment of information about morphology was useful at identifying different type of ion dysfunction [LQT1 (IKs) vs. LQT2 (IKr)].

Further investigation in the congenital LQT2 patients was published by the same group. The role of T-wave morphology was tested for identifying patients carrying a LQT2 mutation but with near-normal QT interval duration. The work suggested that the morphology of the T-wave was helping separating the patients with and without mutation (with and without IKr –inhibited kinetics). It is noteworthy that the part of the T-wave contributing to better identifying the patients with the KCNH2 mutation was the left slope of the T-wave measured on lead II.

Drug induced QT prolongation studies conducted by the University of Rochester Heart Research Follow Up Program (HRFUP)

Drug-induced QT prolongation associated with changes in repolarization has been investigated in healthy individuals exposed to moxifloxacin (the drug used for positive control groups in TQTs).8 The study hypothesized that the DETECTION OF THE presence of moxifloxacin, a fluoroquinolone antibiotic associated with small IKr-inhibitory properties, would be improved when using T-wave morphology in combination with QT prolongation. This retrospective study relied on ECG tracings from 40 individuals recorded during a TQTs. The TQTs was a parallel, placebo-controlled study including 18 females. This retrospective study relied on ECG tracings from 40 individuals recorded during a TQTs. The TQTs was a parallel, placebo-controlled study including 18 females. Moxifloxacin induced significant changes in several ECG parameters including QT and QT apex, and early repolarization duration (ERD30), T wave amplitude, and slopes of the ascending and descending arm of T wave. The model based only on T-wave morphological parameters outperformed the model based on QTc interval. Combining information about repolarization interval duration with T-wave morphology significantly improved the detection of presence of moxifloxacin (p<0.01) as described in Figure 2. Increased sensitivity of our novel ECG method contributes to over 40% reduction in sample size of thorough QT studies as described in the right panel of the Figure 2. As a remark, the morphological feature that was relevant for the identification of the presence of moxifloxacin was the value of the left ascending slope of the T-wave.

TdP, T-wave morphology and repolarization instability

The incidence of TdPs in a general population is believed to be 1 out of 100,000 individuals 40 thus the design of study to obtain a statistically relevant number of event would be extremely expensive and not easily manageable.

Thus, based on the ECG tracings of patients with genetically confirmed LQTS (KCNH2 mutation), the correlation between abnormal T-wave morphology and aborted cardiac arrest or death was investigated. In 405 LQT2 patients with QTc interval >= 440 ms, the T-wave morphology was classified using 4 types: normal, flat, notched and low-amplitude T-wave. In patients with borderline QTc prolongation (440-550 ms, N=281), thirty seven percent of the cohort had abnormal T-wave morphology. A Cox regression analysis revealed that the presence of abnormal T-wave morphology was significantly associated with an increased risk for aborted cardiac arrest and cardiac events (hazard ratio=4.1, p=0.005).

Another recent study relied on a set of standard 12-lead ECG strips recorded in a group of patients with and without history of TdPs from the University of Munich, Germany. The patients were enrolled after being admitted to the University Hospital for documented TdPs in the context of drug with QT-prolonging potential. The patients were enrolled in the study for an evaluation of the individual level of repolarization reserve by challenging it using drug sotalol. We obtained access to 2 ECG tracings per individual at baseline and on peak concentration of the drug. The results suggested that the QT interval duration from the computerized method applied to the first eigenvector (Table 2) was significantly longer within the two groups for QT, QT apex intervals (p<0.01). The prolongation was significantly more pronounced in the group of individuals with history of TdPs (p<0.06) confirming the results from Kaab et al. based on maximum QT interval from all available leads. More interestingly, sotalol significantly prolongs the TpTe interval only in the group with history of TdPs (36±41 vs. 6±20 msec, p=0.01). The measurements of the early and late part of the repolarization interval (ERD and LRD) confirm the observations based on QT, QT apex and TpTe intervals. The sotalol-induced delay of the repolarization is increased in both groups but only the late part of the repolarization process (LRD70%) is significantly longer on the ECGs of individuals with a history of TdPs (27±30 vs. 8±13 msec, p=0.03).

In this study, the beat-to-beat QT variability was measured using the semi-computerized QT interval after heart rate correction based on pooled formula. The median absolute value of the RR intervals (madQTc/madRR) is reported. As shown in Table 2, no difference in levels of QT variability was found in ECG recorded on sotalol between the two groups but the baseline QT variability was significantly larger in patients with history of TdPs (p=0.03).

Table 2: Description of baseline values and sotalol-induced changes in values of electrocardiographic parameters.

 

(-) TdPs: patients without a history of TdPs, (+) TdPs: patients with a history of TdPs. These measurements are corrected using the pooled formula and expressed in milliseconds. TpTe: T peak to T end interval in lead II, ERD: early repolarization duration, LRD: late repolarization duration (for definition of the ERD and LRD parameters see text). madQTc/madRR: ratio of median absolute values of QTc to RR values. * p<0.05 testing that sotalol-induced changes are superior to zero.

This preliminary work has evidenced that the prolongation of the QT intervals is not associated with an evenly distributed delay across the entire repolarization interval. At baseline, a large set of patients with a history of drug-induced TdPs has a specific repolarization profile and an increased instability of the repolarization segment. Interestingly, similarly abnormal T-morphology were observed in ECGs in healthy subjects on moxifloxacin namely changes in morphology prior to the T-wave apex. It is noteworthy that in the analysis of the repolarization process from surface ECGs in LQT2 patients with borderline QT interval duration (390 to 440 msec) compared to family members without the mutation, the same early portion of the T-wave (quantified using left slope of T-wave) was helping to better identify the patients with the mutation.

In this study, the patients had history of TdPs but did not develop TdPs when challenged using sotalol.

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