Tomas Novotny

Subject-specific profiles of QT/RR hysteresis.

The time lag of the QT interval adaptation to heart rate changes (QT/RR hysteresis) was studied in 40 healthy subjects (18 females; mean age, 30.4+/-8.1 yr) with 3 separate daytime (>13 h) 12-lead electrocardiograms (ECG) in each subject. In each recording, 330 individual 10-s ECG segments were measured, including 100 segments preceded by 2 min of heart rate varying greater than +/-2 beats/min. Other segments were preceded by a stable heart rate. In segments preceded by variable rate, QT/RR hysteresis was characterized by lambda parameters of the exponential decay models. The intrasubject SDs of lambda values were compared with the intersubject SD of the individual means. The lambda values were also correlated to individually optimized parameters of heart rate correction. Intrasubject SDs of lambda were substantially smaller than the population SD of individual means (0.390+/-0.197 vs. 0.711, P<0.0001). The lambda values were unrelated to the QT/RR correction parameters. When compared with the corrected QT (QTc) for averaged RR intervals in 10-s ECGs and with the averaged RR intervals in 2-min history, QTc for QT/RR hysteresis led to a substantially smaller SD of QTc values (11.4+/-2.00, 6.33+/-1.31, and 4.66+/-0.85 ms, respectively, P<0.0001). Thus the speed with which the QT interval adapts to heart rate changes is highly individual with intrasubject stability and intersubject variability. QT/RR hysteresis is independent of the static QT/RR relationship and should be considered as a separate physiological process. The combination of individual heart rate correction with individual hysteresis correction of the QT interval is likely to lead to substantial improvements of cardiac repolarization studies.

Towards clinical molecular diagnosis of inherited cardiac conditions: a comparison of bench-top genome DNA sequencers.

Background Molecular genetic testing is recommended for diagnosis of inherited cardiac disease, to guide prognosis and treatment, but access is often limited by cost and availability. Recently introduced high-throughput bench-top DNA sequencing platforms have the potential to overcome these limitations. Methodology/Principal Findings We evaluated two next-generation sequencing (NGS) platforms for molecular diagnostics. The protein-coding regions of six genes associated with inherited arrhythmia syndromes were amplified from 15 human samples using parallelised multiplex PCR (Access Array, Fluidigm), and sequenced on the MiSeq (Illumina) and Ion Torrent PGM (Life Technologies). Overall, 97.9% of the target was sequenced adequately for variant calling on the MiSeq, and 96.8% on the Ion Torrent PGM. Regions missed tended to be of high GC-content, and most were problematic for both platforms. Variant calling was assessed using 107 variants detected using Sanger sequencing: within adequately sequenced regions, variant calling on both platforms was highly accurate (Sensitivity: MiSeq 100%, PGM 99.1%. Positive predictive value: MiSeq 95.9%, PGM 95.5%). At the time of the study the Ion Torrent PGM had a lower capital cost and individual runs were cheaper and faster. The MiSeq had a higher capacity (requiring fewer runs), with reduced hands-on time and simpler laboratory workflows. Both provide significant cost and time savings over conventional methods, even allowing for adjunct Sanger sequencing to validate findings and sequence exons missed by NGS. Conclusions/Significance MiSeq and Ion Torrent PGM both provide accurate variant detection as part of a PCR-based molecular diagnostic workflow, and provide alternative platforms for molecular diagnosis of inherited cardiac conditions. Though there were performance differences at this throughput, platforms differed primarily in terms of cost, scalability, protocol stability and ease of use. Compared with current molecular genetic diagnostic tests for inherited cardiac arrhythmias, these NGS approaches are faster, less expensive, and yet more comprehensive.

The homozygous KCNQ1 gene mutation associated with recessive Romano-Ward syndrome.

In a 7‐year‐old boy with normal hearing suffering from repeated syncope an extremely prolonged QTc interval (up to 700 ms) was found. The mother was completely asymptomatic and the father had an intermittently borderline QTc interval (maximum 470 ms) but no symptoms. In the proband a mutation analysis of KCNQ1 gene revealed a homozygous 1893insC mutation. The parents were heterozygous for this mutation. There was no consanguineous marriage in the family. The clinical relevance of these findings is that apparently normal individuals may have a latent reduction of repolarizing currents, a “reduced repolarization reserve,” because they are carriers of latent ion channel genes mutations.

Dynamic properties of selected repolarization descriptors.

A number of morphological indices have been proposed to characterize electrocardiographic patterns of ventricular repolarization mostly studying spatial and temporal patterns of T waves. Comparisons between different clinical populations exist but data on the suitability of the T-wave descriptors to characterize and quantify physiologic regulations of ventricular repolarization are lacking. To initiate such investigations, a study was conducted comparing the influence of provoked heart rate changes on the duration of QT interval, the roundness of T wave loop expressed by the relative T wave area, and on the 3-dimensional QRS-T angle. A population of 40 healthy subjects (18 women, mean age 30.4 ± 8.1 years) was studied. In each subject, provocative tests involving changes from strict supine to unsupported sitting and to unsupported standing positions were repeated twice during each of 3 separate monitoring days. Continuous 12-lead electrocardiograms were obtained during the provocative tests. The speed of the adaptation of the repolarization descriptors to heart rate changes was characterized by λ parameters of previously published exponential decay model of R-R interval related hysteresis. The comparisons showed that the adaptation of QT interval to heart rate changes was much slower than that of the investigated T-wave morphological descriptors: the mean (SD) values of λ parameters were 5.01 ± 1.13, 12.72 ± 8.66, and 12.90 ± 11.37 for QT interval, QRS-T angle, and relative T-wave area, respectively (P < .001 for the difference between QT interval and both morphological descriptors). The study suggests that the different numerical quantifiers of vertricular repolarization that may be derived from standard electrocardiographic tracings likely represent separate and distinct physiologic entities.

Mutation Analysis Ion Channel Genes Ventricular Fibrillation Survivors with Coronary Artery Disease

Background: Observations from population‐based studies demonstrated a strong genetic component of sudden cardiac death. The aim of this study was to test the hypothesis that ion channel genes mutations are more common in ventricular fibrillation (VF) survivors with coronary artery disease (CAD) compared to controls.

A new homozygous mutation of the KCNQ1 gene associated with both Romano-Ward and incomplete Jervell Lange-Nielsen syndromes in two sisters

The mutations in the KCNQ1 gene (GenBank accession no. AF000571) encoding the subunit of the KCNQ1 channel can cause 2 different diseases: Romano-Ward syndrome (RWS), traditionally described as a combination of repeated syncope episodes and a prolonged QT interval, and the less frequent Jervell and Lange-Nielsen syndrome (JLNS), also associated (except for the abovementioned symptoms) with congenital bilateral deafness.1 The first one is usually associated with the heterozygous gene mutation, the latter one with the homozygous mutation. The disease prevalence is estimated at close to 1 in 2,500 live births, and JLNS has been reported to affect about 3 in 1 million individuals, which represents less than 1% of all long-QT syndrome (LQTS) patients.

Clinical value of different QRS-T angle expressions

Abstract Aims Increased spatial angle between QRS complex and T wave loop orientations has repeatedly been shown to predict cardiac risk. However, there is no consensus on the methods for the calculation of the angle. This study compared the reproducibility and predictive power of three most common ways of QRS-T angle assessment. Methods and results Electrocardiograms of 352 healthy subjects, 941 survivors of acute myocardial infarction (MI), and 605 patients recorded prior to the implantation of automatic defibrillator [implantable cardioverter defibrillator (ICD)] were used to obtain QRS-T angle measurements by the maximum R to T (MRT), area R to T (ART), and total cosine R to T (TCRT) methods. The results were compared in terms of physiologic reproducibility and power to predict mortality in the cardiac patients during 5-year follow-up. Maximum R to T results were significantly less reproducible compared to the other two methods. Among both survivors of acute MI and ICD recipients, TCRT method was statistically significantly more powerful in predicting mortality during follow-up. Among the acute MI survivors, increased spatial QRS-T angle (TCRT assessment) was particularly powerful in predicting sudden cardiac death with the area under the receiver operator characteristic of 78% (90% confidence interval 63–90%). Among the ICD recipients, TCRT also predicted mortality significantly among patients with prolonged QRS complex duration when the spatial orientation of the QRS complex is poorly defined. Conclusion The TCRT method for the assessment of spatial QRS-T angle appears to offer important advantages in comparison to other methods of measurement. This approach should be included in future clinical studies of the QRS-T angle. The TCRT method might also be a reasonable candidate for the standardization of the QRS-T angle assessment.

The role of computerized diagnostic proposals in the interpretation of the 12-lead electrocardiogram by cardiology and non-cardiology fellows

INTRODUCTION Most contemporary 12-lead electrocardiogram (ECG) devices offer computerized diagnostic proposals. The reliability of these automated diagnoses is limited. It has been suggested that incorrect computer advice can influence physician decision-making. This study analyzed the role of diagnostic proposals in the decision process by a group of fellows of cardiology and other internal medicine subspecialties. MATERIALS AND METHODS A set of 100 clinical 12-lead ECG tracings was selected covering both normal cases and common abnormalities. A team of 15 junior Cardiology Fellows and 15 Non-Cardiology Fellows interpreted the ECGs in 3 phases: without any diagnostic proposal, with a single diagnostic proposal (half of them intentionally incorrect), and with four diagnostic proposals (only one of them being correct) for each ECG. Self-rated confidence of each interpretation was collected. RESULTS Availability of diagnostic proposals significantly increased the diagnostic accuracy (p<0.001). Nevertheless, in case of a single proposal (either correct or incorrect) the increase of accuracy was present in interpretations with correct diagnostic proposals, while the accuracy was substantially reduced with incorrect proposals. Confidence levels poorly correlated with interpretation scores (rho≈2, p<0.001). Logistic regression showed that an interpreter is most likely to be correct when the ECG offers a correct diagnostic proposal (OR=10.87) or multiple proposals (OR=4.43). CONCLUSION Diagnostic proposals affect the diagnostic accuracy of ECG interpretations. The accuracy is significantly influenced especially when a single diagnostic proposal (either correct or incorrect) is provided. The study suggests that the presentation of multiple computerized diagnoses is likely to improve the diagnostic accuracy of interpreters.

Clinical characteristics of 30 Czech families with long QT syndrome and KCNQ1 and KCNH2 gene mutations: importance of exercise testing

BACKGROUND Classic symptoms of long QT syndrome (LQTS) include prolongation of QT interval on electrocardiograph, syncope, and cardiac arrest due to a distinctive form of polymorphic ventricular tachycardia, known as Torsade de Pointes. We assessed occurrence of LQTS signs in individuals from 30 Czech families with mutations in KCNQ1 and KCNH2 genes. METHODS AND RESULTS One hundred five individuals from 30 Czech families with LQTS were genotyped for KCNQ1 and KCNH2. The occurrence of typical LQTS signs (pathologic prolongation of QT interval; syncope; cardiac arrest; Torsade de Pointes) was clinically assessed by exercise test with QT interval analysis. Family history of sudden cardiac death was taken. Statistical analysis was performed to determine correlation of clinical results and mutation status. KCNQ1 gene mutations were found in 23 families, and KCNH2 gene mutations in eight families. Only 46 (70%) of the 66 mutation carriers had at least two of the typical LQTS signs. The others were minimally or asymptomatic. From 39 noncarrier individuals, only 1 fulfilled the clinical criteria of LQTS diagnosis, another 4 had an intermediate probability of diagnosis. The exercise test had 92% sensitivity and 93% specificity for LQTS diagnosis. CONCLUSIONS Incidence of classical signs of LQTS was not high in Czech carriers of KCNQ1 and KCNH2 mutations. Therefore, proper diagnosis relies on detection of symptoms at presentation. The exercise test may be beneficial owing to its high sensitivity and specificity for LQTS diagnosis.

Association of the right ventricle impairment with electrocardiographic localization and related artery in patients with ST-elevation myocardial infarction

INTRODUCTION The right ventricular myocardial infarction (RVMI) has traditionally been mainly related to inferior wall ST elevation myocardial infarction (STEMI). This study assessed the RVMI electrocardiographic (ECG-RVMI) signs in relationship to ECG-based STEMI localization and to the infarct related artery in patients treated with primary percutaneous coronary intervention (pPCI). METHODS Three hundred consecutive adult patients (107 females) were referred to catheterization laboratory with the acute STEMI diagnosis. In all patients, both the standard 12-lead ECGs and the right-sided precordial leads (V1R-V6R) were recorded. ECG-RVMI was diagnosed by ST segment elevation above 100μV in V4R. RESULTS ECG signs of RVMI were found in 35 and 31 (23.8% for both) patients with inferior and anterior wall STEMI, respectively. In 32 ECG-RVMI patients, the right coronary artery (RCA) was occluded while in 34 patients, the occlusions were in the left anterior descending (LAD) or the left circumflex artery. No statistically significant differences were found in ECG-RVMI patients when comparing clinical variables between those with anterior and inferior wall STEMI. CONCLUSIONS ECG signs of RVMI during acute STEMI are not uncommon. RCA was the infarction-related artery in only one half of these patients. Anterior wall STEMI and the LAD were associated with a significant proportion of ECG-RVMI cases.