Influence of the training set composition on the estimation performance of linear ECG-lead transformations.

Linear ECG-lead transformations (LELTs) are used to estimate unrecorded target leads by applying a number of recorded basis leads to a LELT matrix. Such LELT matrices are commonly developed using training datasets that are composed of ECGs that belong to different diagnostic classes (DCs). The aim of our research was to assess the influence of the training set composition on the estimation performance of LELTs that estimate target leads V1, V3, V4 and V6 from basis leads I, II, V2 and V5 of the 12-lead ECG. Our assessment was performed using ECGs from the three DCs left ventricular hypertrophy, right bundle branch block and normal (ECGs without abnormalities). Training sets with different DC compositions were used for the development of LELT matrices. These matrices were used to estimate the target leads of different test sets. The estimation performance of the developed matrices was quantified using root mean square error values calculated between derived and recorded target leads. Our findings indicate that unbalanced training sets can lead to LELTs that show large estimation performance variability across different DCs. Balanced training sets were found to produce LELTs that performed well across multiple DCs. We recommend balanced training sets for the development of LELTs

Heart rate dependency of JT interval sections.

BACKGROUND: Little experience exists with the heart rate correction of J-Tpeak and Tpeak-Tend intervals. METHODS: In a population of 176 female and 176 male healthy subjects aged 32.3±9.8 and 33.1±8.4years, respectively, curve-linear and linear relationship to heart rate was investigated for different sections of the JT interval defined by the proportions of the area under the vector magnitude of the reconstructed 3D vectorcardiographic loop. RESULTS: The duration of the JT sub-section between approximately just before the T peak and almost the T end was found heart rate independent. Most of the JT heart rate dependency relates to the beginning of the interval. The duration of the terminal T wave tail is only weakly heart rate dependent. CONCLUSIONS: The Tpeak-Tend is only minimally heart rate dependent and in studies not showing substantial heart rate changes does not need to be heart rate corrected. For any correction formula that has linear additive properties, heart rate correction of JT and JTpeak intervals is practically the same as of the QT interval. However, this does not apply to the formulas in the form of Int/RR(a) since they do not have linear additive properties

Comprehensive T wave Morphology Assessment in a Randomized Clinical Study of Dofetilide, Quinidine, Ranolazine, and Verapamil

Background Congenital long QT syndrome type 2 (abnormal hERG potassium channel) patients can develop flat, asymmetric, and notched T waves. Similar observations have been made with a limited number of hERG-blocking drugs. However, it is not known how additional calcium or late sodium block, that can decrease torsade risk, affects T wave morphology. Methods and Results Twenty-two healthy subjects received a single dose of a pure hERG blocker (dofetilide) and 3 drugs that also block calcium or sodium (quinidine, ranolazine, and verapamil) as part of a 5-period, placebo-controlled cross-over trial. At pre-dose and 15 time-points post-dose, ECGs and plasma drug concentration were assessed. Patch clamp experiments were performed to assess block of hERG, calcium (L-type) and late sodium currents for each drug. Pure hERG block (dofetilide) and strong hERG block with lesser calcium and late sodium block (quinidine) caused substantial T wave morphology changes (P<0.001). Strong late sodium current and hERG block (ranolazine) still caused T wave morphology changes (P<0.01). Strong calcium and hERG block (verapamil) did not cause T wave morphology changes. At equivalent QTc prolongation, multichannel blockers (quinidine and ranolazine) caused equal or greater T wave morphology changes compared with pure hERG block (dofetilide). Conclusions T wave morphology changes are directly related to amount of hERG block; however, with quinidine and ranolazine, multichannel block did not prevent T wave morphology changes. A combined approach of assessing multiple ion channels, along with ECG intervals and T wave morphology may provide the greatest insight into drug-ion channel interactions and torsade de pointes risk

Abdominal Fetal Vectorcardiogram Extraction

Diplomová práce se v teoretické části zabývá prostudováním problematiky zpracování signálu, neinvazivními metodami snímání elektrokardiogramu plodu se zaměřením na metody jednokanálové. Cílem bylo vybrat vhodnou metodu k extrakci plodového EKG, která dokáže plodové EKG extrahovat v dostatečné kvalitě k vykreslení plodového vektorkardiogramu. Po provedené rešerši byla vybrána metoda šablonového odčítání (Template substraction) pro velmi dobré hodnocení extrakce. Cílem praktické části je ověření, zda lze neinvazivním způsobem získat elektrokardiogramy plodu ve třech osách tak, aby mohly být použity pro vykreslení plodového vektorkardiogramu. Dále je pak praktická část pak zaměřena na vygenerování syntetických abdominálních signálů, předzpracování a zpracování abdominálních signálů s následnou extrakcí plodového EKG pěti metodami šablonového odčítání. Experiment byl proveden na umělých datech, generovaných z databáze FECGSYNDB, která umožňuje nastavit velké množství parametrů signálu, vzájemných poměrů mateřského a plodového EKG a různé typy artefaktů. Součástí experimentu je vyhodnocení úspěšnosti jednotlivých metod extrakce porovnáním s originálním plodovým EKG, pomocí střední kvadratické odchylky MSE, směrodatné odchylky RMSE a korelace v každé ose snímání. Toto porovnání bylo umožněno použitím syntetických dat, která při generování abdominálního signálu používá původní, ničím nezkreslený signál plodového EKG. Ten byl při generování uložen a později po extrakci plodového EKG z abdominálního signálu použit ke vzájemnému porovnání. Nejlepší výsledky dosahuje podle MSE metoda SUZANNA, nejlepší korelace mezi původním a extrahovaným signálem je u metody CERUTTI, nelze však říci, že by obě metody byly výrazně lepší než ostatní. Významný rozdíl byl v časové náročnosti, kdy metoda PCA vyžaduje na extrakci čas asi 25x až 40x delší než ostatní metody. Metoda LP při extrakci v určitých místech na konci signálu vykazovala singularitu, což se projevilo i na extrahovaném signálu.In the theoretical part, the diploma thesis deals with the study of signal processing, non-invasive methods of fetal electrocardiogram scanning with a focus on single-channel methods. The aim was to select a suitable method for fetal ECG extraction, which can extract fetal ECG in sufficient quality to plot the fetal vector cardiogram. After the search, the template substraction method was chosen for a very good extraction evaluation. The aim of the practical part is to verify whether the electrocardiograms of the fetus in three axes can be obtained in a non-invasive way so that they can be used to plot the fetal vector cardiogram. Furthermore, the practical part is focused on the generation of synthetic abdominal signals, preprocessing and processing of abdominal signals with subsequent extraction of the fetal ECG by five methods of template subtraction. The experiment was performed on artificial data generated from the FECGSYNDB database, which allows to set a large number of signal parameters, maternal and fetal ECG ratios and different types of artifacts. A part of the experiment is the evaluation of the success of each extraction method by comparison with the original fetal ECG, using the mean square deviation (MSE), the standard deviation (RMSE) and the correlation in each scanning axis. This comparison was allowed by using synthetic data that uses the original, undistorted fetal ECG signal to generate the abdominal signal. This original signal was stored during generation and later, after extraction of the fetal ECG from the abdominal signal, it was used for comparison. According to MSE, the SUZANNA method achieves the best results; the best correlation between the original and extracted signal is by the CERUTTI method, but it cannot be claimed that both methods are significantly better than the others. There was a significant difference in time. The PCA method requires about 25 to 40 times longer extraction time than other methods. The LP method showed a singularity at certain points at the end of the signal, which was also reflected in the extracted signal.450 - Katedra kybernetiky a biomedicínského inženýrstvívýborn

Improving assessment of cardiovascular arrhythmic safety of new pharmacologic agents

Fourteen drugs have been removed from the market worldwide due to an increased risk of torsade de pointes (TdP), a potentially fatal ventricular arrhythmia. Almost all of the removed drugs that have been linked to an increased risk for TdP have been shown to block the human ether-à-go-go-related gene (hERG) potassium channel. In addition, block of the hERG potassium channel results in a prolongation of the duration of ventricular repolarization measured as the QT interval on the electrocardiogram (ECG). Therefore, almost all new drugs must be studied in a thorough QT (TQT) study to determine if they have the potential to prolong the heart rate corrected QT interval (QTc). The TQT study is an expensive study that in addition to including a negative control (placebo), also includes a positive pharmacologic control to ensure assay sensitivity and proper study conduct. Not all drugs that block the hERG potassium channel and prolong the QTc interval have been linked with a risk for TdP likely due to additional inward current block. For example block of the late sodium (amiodarone, ranolazine) or L-type calcium (verapamil). In addition, not every study is able to detect the QTc prolongation associated with the positive pharmacological control. It is unknown which factors have a greater influence on study quality and the ability to demonstrate assay sensitivity. TQT studies from the Food and Drug Administration (FDA) ECGWarehouse were used to investigate factors of assay sensitivity and how they relate to ECG quality metrics, as well as new ECG biomarkers that could complement the QTc interval and increase specificity of the TQT study. In addition, two prospective clinical trials were conducted to evaluate the performance of the new ECG biomarkers. The first clinical trial focuses on comparing selective hERG potassium channel blockers to multichannel blockers. The goal of the second clinical trial is to evaluate if selective late sodium or L-type calcium channel blockers could reduce drug-induced QTc prolongation. Finally, data from the first clinical trial was used to study dynamic ECG biomarkers. The retrospective analysis of TQT studies showed that the most influential factors of assay sensitivity is reader variability and stability of heart rate. The latter being driven in part by study conduct. In addition, the retrospective analysis suggested that by breaking down the QTc interval into QRS, J-Tpeakc and Tpeak-Tend intervals that it is possible to detect the presence of inward current block (late sodium or L-type calcium), that can reduce the risk for TdP. In two prospective clinical studies the proposed ECG biomarkers were shown to be able to detect the presence of inward current block. Moreover, the second clinical trial showed that a selective late sodium current blocker (mexiletine or lidoacaine) shortens dofetilide-induced QTc prolongation. Lastly, using ECG measurements from periods of postural maneuvers and light exercises it was possible to detect the presence of reverse use dependence and increased instability of the QT interval (dynamic ECG biomarkers) associated with hERG potassium channel block. No changes in the dynamic ECG biomarkers was observed with ranolazine, and only small changes was observed with verapamil. Overall, the findings in this thesis show that by ensuring consistently measured QT intervals and maximizing heart rate stability the ability to detect the QTc interval prolongation associated with the positive control is improved. Ensuring consistent QT measurements also results in improved quality of QTc measurements, quantified using QTc quality metrics. In addition, the use of the J-Tpeakc and Tpeak-Tend intervals allows for discrimination between drugs that are selective hERG potassium channel blockers, and are associated with a high risk for TdP, and multichannel blockers with a low risk for TdP