The effect of sex and age on ex vivo cardiac electrophysiology: insight from a guinea pig model.

Highlighting the importance of sex as a biological variable, we recently reported sex differences in guinea pig in vivo electrocardiogram (ECG) measurements. However, substantial inconsistencies exist in this animal model, with conflicting reports of sex-specific differences in cardiac electrophysiology observed in vivo and in vitro. Herein, we evaluated whether sexual dimorphism persists in ex vivo preparations, using an isolated intact heart preparation. Pseudo-ECG recordings were collected in conjunction with dual optical mapping of transmembrane voltage and intracellular calcium from Langendorff-perfused hearts. In contrast to our in vivo results, we did not observe sex-specific differences in ECG parameters collected from isolated hearts. Furthermore, we observed significant age-specific differences in action potential duration (APD) and Ca2+ transient duration (CaD) during both normal sinus rhythm (NSR) and in response to dynamic pacing but only a modest sex-specific difference in CaD30. Similarly, the alternans fluctuation coefficient, conduction velocity during sinus rhythm or in response to pacing, and electrophysiology parameters (atrioventricular nodal effective refractory period, Wenckebach cycle length) were comparable between males and females. Results of our study suggest that the observed sex-specific differences in in vivo ECG parameters from guinea pigs are diminished in ex vivo isolated heart preparations, although age-specific patterns are prevalent. To assess sex as a biological variable in cardiac electrophysiology, a comprehensive approach may be necessary using both in vitro measurements from cardiomyocyte or intact heart preparations with secondary follow-up in vivo studies.NEW & NOTEWORTHY We evaluated whether the guinea pig heart has intrinsic sex-specific differences in cardiac electrophysiology. Although we observed sex-specific differences in in vivo ECGs, these differences did not persist ex vivo. Using a whole heart model, we observed similar APD, CaD, conduction velocity, and alternans susceptibility in males and females. We conclude that sex-specific differences in guinea pig cardiac electrophysiology are likely influenced by the in vivo environment and less dependent on the intrinsic electrical properties of the heart.

Structure and function of the ventricular tachycardia isthmus.

Catheter ablation of postinfarction reentrant ventricular tachycardia (VT) has received renewed interest owing to the increased availability of high-resolution electroanatomic mapping systems that can describe the VT circuits in greater detail, and the emergence and need to target noninvasive external beam radioablation. These recent advancements provide optimism for improving the clinical outcome of VT ablation in patients with postinfarction and potentially other scar-related VTs. The combination of analyses gleaned from studies in swine and canine models of postinfarction reentrant VT, and in human studies, suggests the existence of common electroanatomic properties for reentrant VT circuits. Characterizing these properties may be useful for increasing the specificity of substrate mapping techniques and for noninvasive identification to guide ablation. Herein, we describe properties of reentrant VT circuits that may assist in elucidating the mechanisms of onset and maintenance, as well as a means to localize and delineate optimal catheter ablation targets.

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.

Physiologic lead placement with electroanatomic mapping: A case series.

INTRODUCTION: His bundle pacing (HBP) and left bundle branch area pacing (LBBAP) have emerged as attractive alternatives to traditional biventricular pacing to achieve cardiac resynchronization therapy. Early reported results have been inconsistent, particularly amongst patients in whom initial placement with traditional approaches has been unsuccessful or those with complex anatomy or congenital abnormalities. In this report, we describe the use of three-dimensional electroanatomic mapping (EAM) in five selected cases. METHODS: Five patients from multiple clinical sites underwent EAM-guided HBP or LBBAP by highly trained electrophysiologists with significant experience with conduction system pacing. Each patient in this series underwent EAM-guided conduction system pacing due to complex anatomy and/or prior failed lead implantation. RESULTS: EAM-guided lead implantation was successful in all five cases. Capture thresholds were relatively low and patients continued to have evidence of successful lead implantation with minimum 1-month follow-up. The fluoroscopy time varied, likely owing to the variable complexity of the cases. CONCLUSIONS: The use of EAM, in combination with traditional intracardiac electrograms with or without fluoroscopy, allows more targeted and precise placement of leads for HBP and LBBAP pacing. Further investigation is needed to determine this strategy's long-term performance and to optimize patient selection.

Automated Framework for the Inclusion of a His-Purkinje System in Cardiac Digital Twins of Ventricular Electrophysiology.

Personalized models of cardiac electrophysiology (EP) that match clinical observation with high fidelity, referred to as cardiac digital twins (CDTs), show promise as a tool for tailoring cardiac precision therapies. Building CDTs of cardiac EP relies on the ability of models to replicate the ventricular activation sequence under a broad range of conditions. Of pivotal importance is the His-Purkinje system (HPS) within the ventricles. Workflows for the generation and incorporation of HPS models are needed for use in cardiac digital twinning pipelines that aim to minimize the misfit between model predictions and clinical data such as the 12 lead electrocardiogram (ECG). We thus develop an automated two stage approach for HPS personalization. A fascicular-based model is first introduced that modulates the endocardial Purkinje network. Only emergent features of sites of earliest activation within the ventricular myocardium and a fast-conducting sub-endocardial layer are accounted for. It is then replaced by a topologically realistic Purkinje-based representation of the HPS. Feasibility of the approach is demonstrated. Equivalence between both HPS model representations is investigated by comparing activation patterns and 12 lead ECGs under both sinus rhythm and right-ventricular apical pacing. Predominant ECG morphology is preserved by both HPS models under sinus conditions, but elucidates differences during pacing.

Ventricular arrhythmias ablated successfully in the subvalvular interleaflet triangle between the right and left coronary cusps: Electrophysiological characteristics and catheter ablation.

BACKGROUND: Ventricular arrhythmias (VAs) ablated successfully at the right-left subvalvular interleaflet triangle (R-L ILT) between right and left coronary cusps have not been fully characterized. OBJECTIVE: The purpose of this study was to investigate the electrophysiological characteristics of these VAs and their relationships with the left ventricular (LV) summit. METHODS: Twenty-eight VAs ablated successfully at the R-L ILT were studied. RESULTS: Ninety-six percent of VAs had an early precordial electrocardiographic transition. R-wave amplitude in lead V1 was relatively high (RS morphology, R-wave amplitude 0.35 ± 0.09 mV; R/S ratio 0.35 ± 0.27), whereas the morphology of lead I was R-shaped in 71% and M-shaped in 50% of VAs. Earliest potential was recorded at the R-L ILT in 13 of 28 patients and the left pulmonary sinus cusp (LC) in 6 of 28 patients. Mapping the summit communicating vein (summit-CV) failed because of anatomic or instrumental limitations in these 19 patients. In the other 9 patients, earliest potential was successfully recorded at the summit-CV, while perfect pacemapping was achieved. Poor pace mapping was achieved at the R-L ILT or LC in most patients (27/28). Target site was located at the top of the R-L ILT in all cases. A presystolic potential was present at the target site in 18 of 28 patients. A U-curve via the retrograde method was conventionally used to reach the top of the R-L ILT. CONCLUSION: VAs ablated successfully at the R-L ILT have unique electrophysiological characteristics, and R-L ILT may be an endocardial anatomic ablation target for VAs originating from the base of the LV summit.

Pseudo-elevation of conduction system pacing threshold through parallel connection of an intracardiac electrogram recording system.

Parallel connection of an electrophysiology recording system (EP system) to equipment for conduction system pacing (CSP) has been widely used for fine monitoring of intracardiac electrograms and pacing evaluation. We experienced a case showing unexpected pacing threshold exacerbation under specific conditions when the EP system was connected in parallel. We evaluated the underlying mechanism using an ex vivo model. An ex vivo pacing and intracardiac electrogram monitoring model was generated using an oscilloscope, pacing system analyzer (PSA), EP system, and simulated heart. The discrepancy between expected output at the PSA and the actual measured output value at the simulated heart was measured under various conditions and using various combinations of pacing equipment. Parallel connection of the EP system was associated with reduced electrical output from the PSA as recorded at the simulated heart. The unexpected adverse effects were particularly noticeable when using an RMC-5000 EP system with the pacing function on. The trouble is completely resolved by simply turning off the pacing function of the system. There is a possibility that the EP system might increase the pacing threshold in CSP when the PSA and EP system is are deployed in parallel. The issue may provoke pseudo failure of CSP due to the high pacing threshold. When the RMC-5000 is used for conduction system pacing in parallel with a PSA for the pacing test, the pacing function of RMC-5000 should be turned off.

Radiofrequency Ablation Strategies for Intramural Ventricular Arrhythmias.

Catheter ablation is an established treatment strategy for ventricular arrhythmias. However, the presence of intramural substrate poses challenges with mapping and delivery of radiofrequency energy, limiting overall success of catheter ablation. Advances over the past decade have improved our understanding of intramural substrate and paved the way for innovative treatment approaches. Modifications in catheter ablation techniques and development of novel ablation technologies have led to improved clinical outcomes for patients with ventricular arrhythmias. In this review, we explore mapping techniques to identify intramural substrate and describe available radiofrequency energy delivery techniques that can improve overall success rates of catheter ablation.

Simple electrophysiological predictor of QRS change induced by cardiac resynchronization therapy: A novel marker of complete left bundle branch block.

BACKGROUND: QRS complex shortening by cardiac resynchronization therapy (CRT) has been associated with improved outcomes. OBJECTIVE: We hypothesized that the absence of QRS duration (QRSd) prolongation by right ventricular mid-septal pacing (RVP) may indicate complete left bundle branch block (cLBBB). METHODS: We prospectively collected 12-lead surface electrocardiograms (ECGs) and intracardiac electrograms during CRT implant procedures. Digital recordings were edited and manually measured. The outcome measure was a change in QRSd induced by CRT (delta CRT). Several outcome predictors were investigated: native QRSd, cLBBB (by using Strauss criteria), interval between the onset of the QRS complex and the local left ventricular electrogram (Q-LV), and a newly proposed index defined by the difference between RVP and native QRSd (delta RVP). RESULTS: One hundred thirty-three consecutive patients were included in the study. Delta RVP was 27 ± 25 ms, and delta CRT was -14 ± 28 ms. Delta CRT correlated with native QRSd (r = -0.65), with the presence of ECG-based cLBBB (r = -0.40), with Q-LV (r = -0.68), and with delta RVP (r = 0.72) (P < .00001 for all correlations). In multivariable analysis, delta CRT was most strongly associated with delta RVP (P < .00001), followed by native QRSd and Q-LV, while ECG-based cLBBB became a nonsignificant factor. CONCLUSION: Baseline QRSd, delta RVP, and LV electrical lead position (Q-LV) represent strong independent predictors of ECG response to CRT. The absence of QRSd prolongation by RVP may serve as an alternative and more specific marker of cLBBB. Delta RVP correlates strongly with the CRT effect on QRSd and outperforms the predictive value of ECG-based cLBBB.

Postinfarct ventricular tachycardia substrate: Characterization and ablation of conduction channels using ripple mapping.

BACKGROUND: Conduction channels have been demonstrated within the postinfarct scar and seem to be co-located with the isthmus of ventricular tachycardia (VT). Mapping the local scar potentials (SPs) that define the conduction channels is often hindered by large far-field electrograms generated by healthy myocardium. OBJECTIVE: The purpose of this study was to map conduction channel using ripple mapping to categorize SPs temporally and anatomically. We tested the hypothesis that ablation of early SPs would eliminate the latest SPs without direct ablation. METHODS: Ripple maps of postinfarct scar were collected using the PentaRay (Biosense Webster) during normal rhythm. Maps were reviewed in reverse, and clusters of SPs were color-coded on the geometry, by timing, into early, intermediate, late, and terminal. Ablation was delivered sequentially from clusters of early SPs, checking for loss of terminal SPs as the endpoint. RESULTS: The protocol was performed in 11 patients. Mean mapping time was 65 ± 23 minutes, and a mean 3050 ± 1839 points was collected. SP timing ranged from 98.1 ± 60.5 ms to 214.8 ± 89.8 ms post QRS peak. Earliest SPs were present at the border, occupying 16.4% of scar, whereas latest SPs occupied 4.8% at the opposing border or core. Analysis took 15 ± 10 minutes to locate channels and identify ablation targets. It was possible to eliminate latest SPs in all patients without direct ablation (mean ablation time 16.3 ± 11.1 minutes). No VT recurrence was recorded (mean follow-up 10.1 ± 7.4 months). CONCLUSION: Conduction channels can be located using ripple mapping to analyze SPs. Ablation at channel entrances can eliminate the latest SPs and is associated with good medium-term results.

A novel Ventricular map of Electrograms DUration as a Method to identify areas of slow conduction for ventricular tachycardia ablation: The VEDUM pilot study.

BACKGROUND: Bipolar electrogram (EGM) duration is indicative of local activation property and, if prolonged, is useful to discover areas of slow conduction favoring arrhythmias. OBJECTIVE: The present study aimed to create a map of EGM duration during the ventricular tachycardia (VT) (Ventricular Electrograms DUration as a Method map [VEDUM map]) to verify if the slowest activation area is crucial for reentry and could represent a suitable target for rapid VT interruption during ablation. METHODS: Prospectively 30 patients were enrolled for this study. Twenty-one patients were selected, and 24 VT maps with complete circuit delineation (>90% tachycardia cycle length) were analyzed. Activation and VEDUM maps during VT as well as voltage maps during sinus rhythm were created. RESULTS: Twenty-two of 24 VTs (88%) were interrupted during the first radiofrequency delivery (mean time 7.3 ± 5.4 seconds; range 3-25 seconds) at the area with the longest EGM duration (212 ± 47 ms; range 113-330 ms). The mean percentage of the cycle length of VT covered by the EGM with the longest duration was 58% ± 12%. In 9 patients (37%), the longest EGM was located at the isthmus entrance, at the exit in 7 maps (30%), and the mid-isthmuses in 8 maps (33%). In 6 patients (25%), the EGM covered the full diastolic phase. The mean isthmus width was 28 ± 11 mm (range 16-48 mm; median 25 mm). CONCLUSION: A VEDUM map is highly accurate in defining a conductive vulnerable zone of the VT circuit. The longest EGM duration within the isthmus is highly predictive of rapid VT termination at the first radiofrequency delivery even in the case of large isthmuses.

Analyzing the effect of electrode size on electrogram and activation map properties.

BACKGROUND: Atrial electrograms recorded from the epicardium provide an important tool for studying the initiation, perpetuation, and treatment of AF. However, the properties of these electrograms depend largely on the properties of the electrode arrays that are used for recording these signals. METHOD: In this study, we use the electrode's transfer function to model and analyze the effect of electrode size on the properties of measured electrograms. To do so, we use both simulated as well as clinical data. To simulate electrogram arrays we use a two-dimensional (2D) electrogram model as well as an action propagation model. For clinical data, however, we first estimate the trans-membrane current for a higher resolution 2D modeled cell grid and later use these values to interpolate and model electrograms with different electrode sizes. RESULTS: We simulate electrogram arrays for 2D tissues with 3 different levels of heterogeneity in the conduction and stimulation pattern to model the inhomogeneous wave propagation observed during atrial fibrillation. Four measures are used to characterize the properties of the simulated electrogram arrays of different electrode sizes. The results show that increasing the electrode size increases the error in LAT estimation and decreases the length of conduction block lines. Moreover, visual inspection also shows that the activation maps generated by larger electrodes are more homogeneous with a lower number of observed wavelets. The increase in electrode size also increases the low voltage areas in the tissue while decreasing the slopes and the number of detected deflections. The effect is more pronounced for a tissue with a higher level of heterogeneity in the conduction pattern. Similar conclusions hold for the measurements performed on clinical data. CONCLUSION: The electrode size affects the properties of recorded electrogram arrays which can respectively complicate our understanding of atrial fibrillation. This needs to be considered while performing any analysis on the electrograms or comparing the results of different electrogram arrays.

The isthmus characteristics of scar-related macroreentrant atrial tachycardia in patients with and without cardiac surgery.

INTRODUCTION: Identifying the critical isthmus (CI) in scar-related macroreentrant atrial tachycardia (AT) is challenging, especially for patients with cardiac surgery. We aimed to investigate the electrophysiological characteristics of scar-related macroreentrant ATs in patients with and without cardiac surgery. METHODS: A prospective study of 31 patients (mean age 59.4 ± 9.81 years old) with scar-related macroreentrant ATs were enrolled for investigation of substrate properties. Patients were categorized into the nonsurgery (n = 18) and surgery group (n = 13). The CIs were defined by concealed entrainment, conduction velocity less than 0.3 m/s, and the presence of local fractionated electrograms. RESULTS: Among the 31 patients, a total of 65 reentrant circuits and 76 CIs were identified on the coherent map. The scar in the surgical group is larger than the nonsurgical group (18.81 ± 9.22 vs. 10.23 ± 5.34%, p = .016). The CIs in surgical group have longer CI length (15.27 ± 4.89 vs. 11.20 ± 2.96 mm, p = .004), slower conduction velocity (0.46 ± 0.19 vs. 0.69 ± 0.14 m/s, p < .001), and longer total activation time (45.34 ± 9.04 vs. 38.24 ± 8.41%, p = .016) than those in the nonsurgical group. After ablation, 93.54% of patients remained in sinus rhythm during a follow-up of 182 ± 19 days. CONCLUSION: The characteristics of the isthmus in macroreentrant AT are diverse, especially for surgical scar-related AT. The identification of CIs can facilitate the successful ablation of scar-related ATs.

Persistent atrial fibrillation ablation in cardiac laminopathy: Electrophysiological findings and clinical outcomes.

BACKGROUND: Little is known about persistent atrial fibrillation (AF) ablation in patients with cardiac laminopathy (CLMNA). OBJECTIVES: We aimed to characterize atrial electrophysiological properties and to assess the long-term outcomes of persistent AF ablation in patients with CLMNA. METHODS: All patients with CLMNA referred in our center for persistent AF ablation were retrospectively included. Left atrial (LA) volume, left atrial appendage (LAA) cycle length, interatrial conduction delay, and LA voltage amplitude were analyzed during the ablation procedure. Sinus rhythm maintenance and LA contractile function were assessed during long-term follow-up. RESULTS: From 2011 to 2020, 8 patients were included. The mean age was 47 ± 14 years, and 3 patients (38%) were women. The LA volume was 205.8 ± 43.7 mL; the LAA AF cycle length was 250.7 ± 85.6 ms; and the interatrial conduction delay was 296.5 ± 110.1 ms. Large low-voltage areas (>50% of the LA surface; <0.5 mV electrogram) were recorded in all 8 patients. Two patients had inadvertent LAA disconnection during ablation. All A waves recorded by pulsed Doppler in sinus rhythm were <30 cm/s before and after AF ablation. Early arrhythmia recurrence was recorded in 7 patients (87%) (time to recurrence 4 ± 4 months; 1.5 procedures per patient). After a mean follow-up of 4.4 ± 3.2 years, 4 patients underwent implantable cardioverter-defibrillator therapy for life-threatening ventricular arrhythmia and 3 patients finally underwent heart transplantation. CONCLUSION: Patients with persistent AF afflicted by CLMNA exhibit severe LA impairment because of large low-voltage areas, prolonged conduction velocity, and reduced contractile function. Ablation procedures have a limited effect with a high recurrence rate.