Electrocardiographic Characteristics and Their Correlation with Echocardiographic Alterations in Fabry Disease

Fabry disease (FD) is an X-linked disorder with α-galactosidase A deficiency. Males (>30 years) and females (>40 years) often present with cardiac manifestations, predominantly left ventricular hypertrophy (LVH). The aim of this study was to evaluate electrocardiographic (ECG) characteristics within FD patients to identify gender related differences, and to additionally explore the association of ECG parameters with structural and functional alterations on transthoracic echocardiography (TTE). Retrospective cross-sectional analysis of 45 FD patients with contemporaneous ECG and TTE was performed and compared to age and gender matched healthy controls. FD patients demonstrated alterations in several ECG parameters particularly in males, including prolonged P-wave duration (91 vs. 81 ms, p = 0.022), prolonged QRS duration (96 vs. 84 ms, p < 0.001), increased R-wave amplitude in lead I (8.1 vs. 5.7 mV, p = 0.047), increased Sokolow–Lyon index (25 vs. 19 mV, p = 0.002) and were more likely to meet LVH criteria (31% vs. 7%, p = 0.006). FD patients with impaired basal longitudinal strain (LS) on TTE were more likely to meet LVH criteria (41% vs. 0%, p = 0.018). Those with more advanced FD (increased LV wall thickness on TTE) were more likely to meet LVH criteria but additionally demonstrated prolonged ventricular depolarization (QRS duration 101 vs. 88 ms, p = 0.044). Therefore, alterations on ECG demonstrating delayed atrial activation, delayed ventricular depolarization and evidence of LVH were more often seen in male FD patients. Impaired basal LS, a TTE marker of early cardiac involvement, correlated with ECG abnormalities. Increased LV wall thickness on TTE, a marker of more advanced FD, was associated with more severe ECG abnormalities.

Left Ventricular Myocardial Septal Pacing in Close Proximity to LBB Does Not Prolong the Duration of the Left Ventricular Lateral Wall Depolarization Compared to LBB Pacing

Background: Three different ventricular capture types are observed during left bundle branch pacing (LBBp). They are selective LBB pacing (sLBBp), non-selective LBB pacing (nsLBBp), and myocardial left septal pacing transiting from nsLBBp while decreasing the pacing output (LVSP). Study aimed to compare differences in ventricular depolarization between these captures using ultra-high-frequency electrocardiography (UHF-ECG).Methods: Using decremental pacing voltage output, we identified and studied nsLBBp, sLBBp, and LVSP in patients with bradycardia. Timing of ventricular activations in precordial leads was displayed using UHF-ECGs, and electrical dyssynchrony (e-DYS) was calculated as the difference between the first and last activation. The durations of local depolarizations (Vd) were determined as the width of the UHF-QRS complex at 50% of its amplitude.Results: In 57 consecutive patients, data were collected during nsLBBp (n = 57), LVSP (n = 34), and sLBBp (n = 23). Interventricular dyssynchrony (e-DYS) was significantly lower during LVSP −16 ms (−21; −11), than nsLBBp −24 ms (−28; −20) and sLBBp −31 ms (−36; −25). LVSP had the same V1d-V8d as nsLBBp and sLBBp except for V3d, which during LVSP was shorter than sLBBp; the mean difference −9 ms (−16; −1), p = 0.01. LVSP caused less interventricular dyssynchrony and the same or better local depolarization durations than nsLBBp and sLBBp irrespective of QRS morphology during spontaneous rhythm or paced QRS axis.Conclusions: In patients with bradycardia, LVSP in close proximity to LBB resulted in better interventricular synchrony than nsLBBp and sLBBp and did not significantly prolong depolarization of the left ventricular lateral wall.

Genetic analyses of the QT interval and its components in over 250K individuals identifies new loci and pathways affecting ventricular depolarization and repolarization

The QT interval is an electrocardiographic measure representing the sum of ventricular depolarization (QRS duration) and repolarization (JT interval). Abnormalities of the QT interval are associated with potentially fatal ventricular arrhythmia. We conducted genome-wide multi-ancestry analyses in >250,000 individuals and identified 177, 156 and 121 independent loci for QT, JT and QRS, respectively, including a male-specific X-chromosome locus. Using gene-based rare-variant methods, we identified associations with Mendelian disease genes. Enrichments were observed in established pathways for QT and JT, with new genes indicated in insulin-receptor signalling and cardiac energy metabolism. In contrast, connective tissue components and processes for cell growth and extracellular matrix interactions were significantly enriched for QRS. We demonstrate polygenic risk score associations with atrial fibrillation, conduction disease and sudden cardiac death. Prioritization of druggable genes highlighted potential therapeutic targets for arrhythmia. Together, these results substantially advance our understanding of the genetic architecture of ventricular depolarization and repolarization.

Investigation of Inaccuracies in the Assessment of Ventricular Late Potentials Using 12-lead ECG Recordings

Introduction. Ventricular late potentials (VLP) are predictors of cardiac disorders such as sudden death syndrome, myocardial infarction and ventricular tachyarrhythmias. Therefore, VLP assessment allows the severity and possible dangerous consequences of such disorders to be predicted.Aim. To determine errors associated with VLP assessment by high-resolution 12-lead ECG recordings.Materials and methods. VLPs were determined by the modulus of the cardiac electrical vector using signals from orthogonal leads. The conversion error was assessed using synchronous ECG recordings of 12-channel and orthogonal leads, the method of digital filtering (to reduce noise and interference) and the method of identifying characteristic points of the QRS complex and VLPs.Results. The conversion of 12-lead ECG signals into orthogonal signals results in errors associated with the assessment of both the modulus of the cardiac electrical vector and all VLP indicators. The Kors transformation was shown to provide the minimum errors when assessing the cardiac electrical vector modulus in the QRS area, with the errors related to the VRMS assessment not exceeding 0.084 %. The estimation of the QRSd and LAS errors should consider the nature of VLP variations and the zone of uncertainty in their assessment. The ambiguity of the results of assessing the boundaries of violations and the absence of pathologies in cardiac ventricular depolarization indicates the influence of a large number of factors on research accuracy. Errors in the assessment of these factors may result in under- and overestimation of dangerous heart rhythm disturbances and incorrect prediction of the patient' state.Conclusion. The obtained results can be used for reducing errors associated with the assessment of VLP indicators, improving the diagnostic accuracy of dangerous heart rhythm disturbances and predicting disease exacerbation due to structural and morphological disorders of the myocardium.

Direct capture of the left bundle branch compared to left bundle branch area pacing deteriorates interventricular synchrony but improves left ventricular lateral wall depolarization duration

Funding Acknowledgements Type of funding sources: Public Institution(s). Main funding source(s): This paper was supported by the Charles University Research Centre program No. UNCE/MED/002 and 260530/SVV/2020 Background Direct and indirect pacing of the left bundle branch are novel pacing techniques preserving LV synchrony. Aim of the study was to compare differences in ventricular activation between them using an UHF-ECG. Methods The left septal lead placement was done in 68 patients with bradycardia. Four distinct ventricular captures were described; nonselective LBBp (nsLBBp), selective LBBp (sLBBp), paraLBBp and left bundle branch area capture (LBBap). The timings of local ventricular activations and local depolarization durations were displayed by the UHF-ECG. e-DYS was calculated as a difference between the first and last activation. Results There were 35 nsLBBp, 21 paraLBBp, 12 sLBBp and 96 LBBap obtained in 68 patients. The nsLBBp compared to LBBap caused worse interventricular synchrony (e-DYS -23 ms (-28;-18) vs -12 ms (-17;-8), p &lt; 0.001), but improved LV lateral wall depolarization duration. The sLBBp, nsLBBp and paraLBBp differed in e-DYS; -31 ms (-38;-24) vs -23 ms (-28;-17) vs -13 ms (-20;-7), p &lt; 0.01 between each of them. Their left ventricular depolarization durations were the same, but they were longer when pacing resulted in the left axis deviation. If the direct capture of the LBB was not confirmed (LBBap), LV depolarization duration was deteriorated irrespective of the QSR morphology in the V1 or RWPT in the V5. Examples of UHF-ECG maps during LBBap, paraLBBp and nsLBBp are shown in Figure 1. Conclusions The direct capture of the left bundle branch deteriorates interventriclar synchrony but improves the depolarization duration of the left ventricular lateral wall compared to left ventricular myocardial septal pacing. Abstract Figure 1

The Evolution of the Neonatal QRS Axis during the First Four Weeks of Life

Background: The QRS axis represents the sum and orientation of the ventricular depolarization. Accurate interpretation of abnormalities in the QRS axis may facilitate early diagnosis of heart disease in newborns. We aimed at describing the evolution of the QRS axis during the first 4 weeks of life and provide reference values from healthy newborns. Methods: The Copenhagen Baby Heart Study is a prospective general population study that offered cardiac evaluation during the first month of life to all newborns delivered in the Copenhagen area. Results: Electrocardiograms from 12,317 newborns (52% boys; mean age 12 days) with normal echocardiograms were included. The median QRS axis was 119° at the ages 0–7 days and shifted leftward to 102° at the ages 22–28 days (p < 0.001). We found that girls had a significantly less pronounced right-shifted axis than boys (p < 0.001) and that increasing gestational age (GA) was associated with a more pronounced right-shifted axis (p < 0.05). Infant size did not affect the axis (p > 0.05). Only 0.5% had an axis within the interval 0 to −90° and 1.1% in the interval +240 to +30°. Conclusions: The QRS axis showed a gradual leftward-shift during the first 4 weeks of life and was affected by sex and GA but unaffected by infant size. Less than 1% of the newborns had a QRS axis between 0 and −90°. This study represents updated reference values, which may facilitate the clinical handling of newborns.

Bivariate Entropy Analysis of Electrocardiographic RR–QT Time Series

QT interval variability (QTV) and heart rate variability (HRV) are both accepted biomarkers for cardiovascular events. QTV characterizes the variations in ventricular depolarization and repolarization. It is a predominant element of HRV. However, QTV is also believed to accept direct inputs from upstream control system. How QTV varies along with HRV is yet to be elucidated. We studied the dynamic relationship of QTV and HRV during different physiological conditions from resting, to cycling, and to recovering. We applied several entropy-based measures to examine their bivariate relationships, including cross sample entropy (XSampEn), cross fuzzy entropy (XFuzzyEn), cross conditional entropy (XCE), and joint distribution entropy (JDistEn). Results showed no statistically significant differences in XSampEn, XFuzzyEn, and XCE across different physiological states. Interestingly, JDistEn demonstrated significant decreases during cycling as compared with that during the resting state. Besides, JDistEn also showed a progressively recovering trend from cycling to the first 3 min during recovering, and further to the second 3 min during recovering. It appeared to be fully recovered to its level in the resting state during the second 3 min during the recovering phase. The results suggest that there is certain nonlinear temporal relationship between QTV and HRV, and that the JDistEn could help unravel this nuanced property.

Pacing of the interventricular septum with His bundle engagement, unlike myocardial pacings of the right ventricle, does not lead to ventricular dyssynchrony, as assessed by ultra-high frequency ECG

Background Nonselective pacing of the distal His bundle is practically just another way of right ventricular septal pacing. It leads to the concomitant activation of the His bundle and septal myocytes with unknown impact on ventricular synchrony. Ultra-high frequency ECG (UHF-ECG) is a novel tool for ventricular depolarization imaging. Purpose To describe ventricular depolarization patterns during nonselective pacing of a ventricular aspect of His bundle and myocardial captures from different locations in the right ventricle by using the UHF-ECG. Methods Consecutive patients with an indication for permanent pacing due to bradycardia were included. During pacemaker implantation, the pacing lead was temporarily placed in prespecified locations of the right ventricle (mid-septum, anterior, lateral wall, and the para-hisian area of the RV). When pacing from mentioned locations, myocardial activation time under each specific lead (Vd), and ventricular dyssynchrony (e-DYS) indexes were calculated from UHF-ECG maps, for each particular type of pacing. The demonstration of UHF-ECG maps during pacing from different locations of the right ventricle is shown in the figure. Results Two hundred and fifty UHF ECG recordings were performed in forty-six patients. The calculated mean e-DYS parameter was significantly shorter during non-selective capture of the distal His bundle (14±8 ms) compared to each of myocardial captures of the right ventricle (pure myocardial para-hisian; 35±12 ms, mid-septal; 28±11 ms, anterior wall; 51±16 ms and lateral wall; 62±19 ms (p&lt;0.001). The Vd was also shortest during non-selective capture of the distal His bundle (39±5 ms) compared to each of the others (pure myocardial para-hisian; 52±11 ms, RV mid-septal; 57±11 ms, RV anterior wall; 68±12 ms and RV lateral wall pacing; 85±14 ms (p&lt;0.001). Conclusion Pacing of the basal interventricular septum with the engagement of the His bundle produced a superior depolarization pattern in both heart ventricles compared to other types of right ventricular myocardial capture, as assessed using UHF-ECG. Figure 1. Examples of UHF-ECG depolarization maps of different types of ventricular activation in the same patient. Funding Acknowledgement Type of funding source: Public Institution(s). Main funding source(s): Charles University in Prague

Concentration-dependent mortality of chloroquine in overdose

Hydroxychloroquine and chloroquine are used extensively in malaria and rheumatological conditions, and now in COVID-19 prevention and treatment. Although generally safe they are potentially lethal in overdose. In-vitro data suggest that high concentrations and thus high doses are needed for COVID-19 infections, but as yet there is no convincing evidence of clinical efficacy. Bayesian regression models were fitted to survival outcomes and electrocardiograph QRS durations from 302 prospectively studied French patients who had taken intentional chloroquine overdoses, of whom 33 died (11%), and 16 healthy volunteers who took 620 mg base chloroquine single doses. Whole blood concentrations of 13.5 µmol/L (95% credible interval 10.1–17.7) were associated with 1% mortality. Prolongation of ventricular depolarization is concentration-dependent with a QRS duration >150 msec independently highly predictive of mortality in chloroquine self-poisoning. Pharmacokinetic modeling predicts that most high dose regimens trialled in COVID-19 are unlikely to cause serious cardiovascular toxicity.