Safe electrophysiologic profile of dexmedetomidine in different experimental arrhythmia models

Previous studies suggest an impact of dexmedetomidine on cardiac electrophysiology. However, experimental data is sparse. Therefore, purpose of this study was to investigate the influence of dexmedetomidine on different experimental models of proarrhythmia. 50 rabbit hearts were explanted and retrogradely perfused. The first group (n = 12) was treated with dexmedetomidine in ascending concentrations (3, 5 and 10 µM). Dexmedetomidine did not substantially alter action potential duration (APD) but reduced spatial dispersion of repolarization (SDR) and rendered the action potentials rectangular, resulting in no proarrhythmia. In further 12 hearts, erythromycin (300 µM) was administered to simulate long-QT-syndrome-2 (LQT2). Additional treatment with dexmedetomidine reduced SDR, thereby suppressing torsade de pointes. In the third group (n = 14), 0.5 µM veratridine was added to reduce the repolarization reserve. Further administration of dexmedetomidine did not influence APD, SDR or the occurrence of arrhythmias. In the last group (n = 12), a combination of acetylcholine (1 µM) and isoproterenol (1 µM) was used to facilitate atrial fibrillation. Additional treatment with dexmedetomidine prolonged the atrial APD but did not reduce AF episodes. In this study, dexmedetomidine did not significantly alter cardiac repolarization duration and was not proarrhythmic in different models of ventricular and atrial arrhythmias. Of note, dexmedetomidine might be antiarrhythmic in acquired LQT2 by reducing SDR.

Moderate Hypothermia Attenuates Pro-Arrhythmic Electromechanical Relations in the Left Ventricle – A Clinical Study

BackgroundTargeted temperature management is recommended after cardiac arrest, but the beneficial effects are controversial. The recently published TTM2 study reports that arrhythmias causing hemodynamic compromise are more common during moderate hypothermia. The causation is not explored. Experimentally, moderate hypothermia attenuates electromechanical relations with pro-arrhythmic impact. Mechanical systole outlasts the electrical systole to a greater extent giving increased electromechanical window positivity, and dispersion of electrical and mechanical activity are unaltered. In this prospective clinical study, we explored the effect of moderate hypothermia on electromechanical relations in un-insulted left ventricles. We hypothesized that during moderate hypothermia, prolongation of systolic duration would exceed electrical duration without dispersed electrical- or mechanical activity. Methods20 patients with normal left ventricular function, undergoing surgery on the ascending aorta and connected to cardiopulmonary bypass, were included. Measurements were obtained at 36 °C and 32 °C prior to aortic-repair, and at 36 °C after repair at spontaneous and paced heart rate 90 bpm. Comparable loading conditions were ensured and cardiopulmonary bypass was reduced to 20% of estimated maximum during the measurements. Global cardiac function was measured invasively and with echocardiography. Electromechanical window, dispersion of repolarization by ECG and mechanical dispersion by echocardiography, were calculated. ResultsAt moderate hypothermia (32°C), mechanical systolic prolongation exceeded electrical prolongation so that electromechanical window increased (29 ± 30 to 86 ± 50 ms, p <0.001). Dispersion of repolarization and mechanical dispersion remained unchanged. Myocardial function was preserved with maintained strain, fractional shortening and stroke volume. Similar electromechanical relations were present also at comparable increased heart rate during moderate hypothermia. After rewarming to 36°C, electromechanical alterations were reversed. ConclusionModerate hypothermia increased electromechanical window positivity. Dispersion of repolarisation, mechanical dispersion, and myocardial function were unchanged. Moderate hypothermia did not induce adverse electromechanical changes in the left ventricle during standardized conditions, but rather an attenuation of pro-arrhythmic electromechanical relations.

Gender differences in ECG markers of increased risk for malignant arrhythmias, peripheral blood parameters, and adverse outcomes in patients with COVID-19 pneumonia

Background: The available data on gender differences in a) markers of cardiac involvement, b) peripheral blood parameters, and c) clinical adverse outcomes related to COVID-19 pneumonia severity are limited in the literature.: Objectives: To investigate gender differences in ECG markers of increased risk for malignant arrhythmias. This includes T from peak to end (Tp-e) interval, corrected QT (QTc), transmural dispersion of repolarization (TDR)(Tp-e/QTc), and index of cardiac electrophysiological balance (iCEB)(QTc/QRS), peripheral blood parameters, and in-hospital adverse outcomes in patients with COVID-19 pneumonia. Methods: A cross sectional study enrolled patients with COVID-19 pneumonia admitted to hospital from August 20th, to September 30th, 2020. Results: A total of 197 patients were included. Ninety-six (47%) were men and 101 women. There were no significant gender related differences concerning comorbidities. Men had higher QRS values, Tp-e interval and TDR, and lower values of iCEB. No significant gender differences were observed in the distribution of QTc interval. Men stayed longer in the hospital and had more extensive lung injury than women. In men, prolonged QTc interval, low lymphocytes %, high platelet distribution width (PDW), and low hemoglobin (Hb) were the main predictors of adverse in-hospital outcome, while prolonged QTc interval, high PDW, and low platelet count were the main predictors of adverse in-hospital outcome for women. Conclusions: Men had higher TDR values, lower iCEB, stayed longer in the hospital, and had more extensive lung injury than women, suggesting that, despite that there was no significant difference in mortality incidents between the two genders, the difference in surrogate markers may indicate that men are at a higher risk for adverse outcomes.

Interplay between temporal and spatial dispersion of repolarization in the initiation and perpetuation of Torsades de Pointes in the chronic AV-block dog

Ventricular arrhythmias, consisting of single ectopic beats (sEB), multiple EB (mEB), and Torsades de Pointes (TdP, defined as >5 beats with QRS vector twisting around isoelectric line) can be induced in the anesthetized chronic AV-block (CAVB) dog by dofetilide (IKr-blocker). The interplay between temporal dispersion of repolarization, quantified as short-term variability (STV), and spatial dispersion of repolarization (SDR) in the initiation and perpetuation of these arrhythmias remains unclear. Five inducible (>3 TdPs/10') CAVB dogs were observed for 10' from the start of dofetilide infusion (0.025mg/kg, 5'). An intracardiac decapolar electrogram (EGM) catheter and 30 intramural cardiac needles in the left ventricle (LV) were introduced. STVARI was derived from 31 consecutive activation recovery intervals (ARI) on the intracardiac EGM, using the formula: . The mean SDR3D in the LV was determined as the three-dimensional repolarization time differences between the intramural cardiac needles. Moments of measurement included baseline (BL) and after dofetilide infusion prior to first 1) sEB (occurrence at 100±35"), 2) mEB (224±96"), and 3) non self-terminating TdP (454±298"). STVARI increased from 2.15±0.32ms at BL to 3.73±0.99ms* prior to the first sEB and remained increased without further significant progression to mEB (4.41±0.45ms*) and TdP (5.07±0.84ms*) (*p<0.05 compared to BL). SDR3D did not change from 31±11ms at BL to 43±13ms prior to sEB, but increased significantly prior to mEB (68±7ms*) and to TdP (86±9ms*+) (+p<0.05 compared to sEB). An increase in STV contributes to the initiation of sEB whereas an increase in SDR is important for the perpetuation of non self-terminating TdPs.

Clinical and Functional Genetic Characterization of the Role of Cardiac Calcium Channel Variants in the Early Repolarization Syndrome

Background: Early repolarization syndrome (ERS) is an inherited sudden cardiac death (SCD) syndrome. The present study investigates the role of genetic variants in cardiac calcium-channel genes in the pathogenesis of ERS and probes the underlying mechanisms.Methods: Polymerase chain reaction–based next-generation sequencing was carried out using a targeted gene approach. Unrelated ERS probands carrying calcium-channel variants were evaluated clinically and compared with matched healthy controls. Wild-type (WT) and mutant CACNA1C genes were coexpressed with CACNB2b and CACNA2D1 in HEK293 cells and studied using whole-cell patch-clamp techniques and confocal fluorescence microscope.Results: Among 104 ERS probands, 16 carried pathogenic variants in calcium-channel genes (32.2 ± 14.6 years old, 87.5% male). The symptoms at diagnosis included syncope (56.3%), ventricular tachycardia/fibrillation (62.5%), and SCD (56.3%). Three cases (18.8%) had a family history of SCD or syncope. Eight patients (50.0%) had a single calcium gene rare variant. The other half carried rare variants in other ERS-susceptible genes. Compared with controls, the heart rate was slower (72.7 ± 8.9 vs. 65.6 ± 16.1 beats/min, *p &lt; 0.05), QTc interval was shorter (408.2 ± 21.4 vs. 386.8 ± 16.9 ms, **p &lt; 0.01), and Tp-e/QT was longer (0.22 ± 0.05 vs. 0.28 ± 0.04, ***p &lt; 0.001) in single calcium mutation carriers. Electrophysiological analysis of one mutation, CACNA1C-P817S (c.2449C&gt;T), revealed that the density of whole-cell calcium current (ICa) was reduced by ~84.61% compared to WT (−3.17 ± 2.53 vs. −20.59 ± 3.60 pA/pF, n = 11 and 15, respectively, **p &lt; 0.01). Heterozygous expression of mutant channels was associated with a 51.35% reduction of ICa. Steady-state inactivation was shifted to more negative potentials and significantly accelerated as well. Confocal microscopy revealed trafficking impairment of CACNA1C-P817S (peripheral/central intensity: 0.94 ± 0.10 in WT vs. 0.33 ± 0.12 in P817S, n = 10 and 9, respectively, **p &lt; 0.01).Conclusions: ERS associated with loss-of-function (LOF) genetic defects in genes encoding the cardiac calcium channel represents a unique clinical entity characterized by decreased heart rate and QTc, as well as increased transmural dispersion of repolarization. In the case of CACNA1C-P817S, impaired trafficking of the channel to the membrane contributes to the LOF.

Standard ECG in Brugada Syndrome as a Marker of Prognosis: From Risk Stratification to Pathophysiological Insights

Background The 12‐lead ECG plays a key role in the diagnosis of Brugada syndrome (BrS). Since the spontaneous type 1 ECG pattern was first described, several other ECG signs have been linked to arrhythmic risk, but results are conflicting. Methods and Results We performed a systematic review to clarify the associations of these specific ECG signs with the risk of syncope, sudden death, or equivalents in patients with BrS. The literature search identified 29 eligible articles comprising overall 5731 patients. The ECG findings associated with an incremental risk of syncope, sudden death, or equivalents (hazard ratio ranging from 1.1–39) were the following: localization of type 1 Brugada pattern (in V2 and peripheral leads), first‐degree atrioventricular block, atrial fibrillation, fragmented QRS, QRS duration >120 ms, R wave in lead aVR, S wave in L1 (≥40 ms, amplitude ≥0.1 mV, area ≥1 mm 2 ), early repolarization pattern in inferolateral leads, ST‐segment depression, T‐wave alternans, dispersion of repolarization, and Tzou criteria. Conclusions At least 12 features of standard ECG are associated with a higher risk of sudden death in BrS. A multiparametric risk assessment approach based on ECG parameters associated with clinical and genetic findings could help improve current risk stratification scores of patients with BrS and warrants further investigation. Registration URL: https://www.crd.york.ac.uk/prospero/ . Unique identifier: CRD42019123794.

Ventricular repolarization homogeneity in transthyretin cardiac amyloidosis

Funding Acknowledgements Type of funding sources: None. Background Non-sustained ventricular tachycardia is frequently observed in patients with transthyretin cardiac amyloidosis (TTR-CA); however, the incidence of sudden tachyarrhythmic death is low. Homogeneity of amyloid fibril deposition within the myocardium and conduction system may mitigate against sustained ventricular tachyarrhythmias. In contrast, myocardial scar heterogeneity is an established predictor of sudden cardiac death in conditions such as hypertrophic cardiomyopathy (HCM), as evidenced by increased myocardial dispersion of repolarization. Whether such indices of arrhythmogenesis are evident in TTR-CA has not been established. Purpose To compare ventricular repolarization indices in TTR-CA to HCM and controls without known cardiovascular disease. Methods We identified TTR-CA and HCM patients from our single center respective registries, and control patients from our clinical ECG database. Only patients in normal sinus rhythm without bundle branch block, cardiac pacing or artifact were included for analysis. Demographic and clinical data were abstracted. ECGs were analyzed at 25 mm/s paper speed and 10 mm/mV amplitude. ECG parameters included QT interval, QT dispersion, and T peak to T end (TpTe) using the tangent method. All measurements were performed by two blinded independent cardiologists. Results A total of 112 patients (45 TTR-CA, 32 HCM, and 35 controls) were studied. Despite a longer QTc in TTR-CA (468.4 ms in TTR-CA vs. 424.6 in controls; p &lt; 0.001), patients with TTR-CA demonstrated similar repolarization indices as controls, including TpTE (93.0 ± 13.5 ms in TTR-CA vs 86.4 ± 12.2 ms in controls, p = 0.24), and TpTe/QTc (0.20 ± 0.03 in TTR-CA vs 0.2 ± 0.03 in controls, p = 0.99). In contrast, HCM patients demonstrated greater TpTe and TpTe/QTc compared with controls (Figure). and a trend toward increased QT dispersion in HCM vs. TTR-CA (p = 0.06). Conclusion Unlike HCM, patients with TTR-CA demonstrate a relative lack of myocardial repolarization heterogeneity compared with controls. This finding correlates with homogeneous distribution of myocardial amyloid fibrils and may explain the low observed incidence of sudden cardiac death in this population. Abstract Figure

Short-term variability of repolarization is equally modulated by atrial and (bi)ventricular high rate pacing in patients with an indication for an implantable cardioverter defibrillator

Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Dutch Heart Foundation Background An increase in temporal dispersion of repolarization, quantified as short-term variability of the QT-interval (STV-QT), precedes ventricular arrhythmias and has therefore been proposed as a marker for monitoring of imminent arrhythmic risk. A reversal of an increased STV by high rate pacing at 100 bpm was anti-arrhythmic in the chronic atrioventricular block dog model susceptible to Torsade de Pointes arrhythmias upon challenge with an IKr-blocker. The objective of the current study was to investigate the physiological modulation of STV by pacing in patients with an indication for an implantable cardioverter defibrillator (ICD), and to compare atrial and ventricular pacing. Methods ECG recordings were obtained with a sampling frequency of 1200 Hz in 10 dual chamber ICD patients and 10 patients with cardiac resynchronization therapy with defibrillation function (CRT-D) during the implantation or replacement. One-minute recordings were made during sinus rhythm (SR), and during pacing at 80 and 100 beats per minute (bpm) from the atrium (AAI), atrium and right ventricle (DDD RVp), and during atrio-biventricular pacing (DDD BiVp). The QT-interval was determined offline with fiducial segment averaging at one minute of each pacing rate, and 31 consecutive beats were used to calculate STV-QT with the following formula: ∑|D(n + 1)-Dn |/(N×√2), where D represents the determinant of repolarization (in this case the QT interval), and N represents the number of beats taken into account minus 1. Results In the patients overall, STV-QT decreased from 1.27 ± 0.38 ms in SR (±58 bpm) to 0.86 ± 0.26 ms* during AAI80, and to 0.68 ± 0.22 ms*† during AAI100 (*p &lt; 0.05 compared to SR, †p &lt; 0.05 compared to 80 bpm). The same decrease was seen during DDD80 RVp (0.81 ± 0.28 ms*) and during DDD100 RVp (0.66 ± 0.22 ms*†) (fig. 1). Additionally, DDD BiVp decreased STV-QT to 0.78 ± 0.20 ms* at 80 bpm and to 0.62 ± 0.19 ms* at 100 bpm in CRT-D patients (fig. 2). Conclusion Pacing at 80 and 100 bpm decreases STV-QT compared to sinus rhythm both in dual chamber ICD patients and CRT-D patients. The modulation of STV-QT is similar during atrial, and atrio- right ventricular and atrio-biventricular pacing. Abstract Figure. Modulation of STV-QT by AAI and DDD RVp

Repolarization characteristics indicate electrical instability in ventricular arrhythmia originating from papillary muscle

Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): DZHK (German Center for Cardiovascular Research) Introduction Cardiac arrhythmia originating from the papillary muscle can trigger ventricular fibrillation and cause sudden cardiac death even in the absence of structural heart disease. Yet, no clinical parameters are known to reflect the propensity of arrhythmia to degenerate into ventricular fibrillation. Purpose We aimed at identification of parameters associated with degeneration of ventricular arrhythmia into ventricular fibrillation. Methods Ventricular arrhythmia was induced by aconitine injection into the papillary muscle of healthy sheep (n = 12) in an open-chest model. Endocardial high-density-mapping and epicardial mapping were performed. We determined repolarization time and activation-recovery-interval according to the Wyatt method. Results During focal arrhythmia faster conduction occurred in longitudinal and basal direction than transversal and apical direction. The electrical restitution curve, modelling relation of diastolic interval and activation-recovery-interval, is steeper in aconitine-induced ventricular arrhythmia than in ventricular pacing or sinus rhythm. Steeper restitution curves reflect electrical instability and propensity to degenerate into ventricular fibrillation. The repolarization-related parameters activation-recovery interval and repolarization time exhibit higher heterogeneity per beat in ventricular arrhythmia preceding degeneration into ventricular fibrillation. Repolarization time in relation to cycle length (RT/CL), which can easily be measured during electrophysiological procedures, differentiates self-limiting from degenerating arrhythmia with high specificity and sensitivity. Conclusion In structurally normal ovine hearts, the ratio of repolarization and cycle length (RT/CL) in ventricular arrhythmia and greater dispersion of repolarization are indicators of subsequent degeneration into ventricular fibrillation. While dispersion of repolarization is not easily acquired in clinical routine, a simple index (RT/CL) may be sufficient to differentiate between self-limiting and electrically instable arrhythmia with propensity to degenerate to ventricular fibrillation. Abstract Figure. Repolarization in VA model