Spectral characterisation of ventricular intracardiac potentials in human post-ischaemic bipolar electrograms

Abnormal ventricular potentials (AVPs) are frequently referred to as high-frequency defections in intracardiac electrograms (EGMs). However, no scientifc study performed a deep spectral characterisation of AVPs and physiological potentials in real bipolar intracardiac recordings across the entire frequency range imposed by their sampling frequency. In this work, the power contributions of post-ischaemic physiological potentials and AVPs, along with some spectral features, were evaluated in the frequency domain and then statistically compared to highlight specific spectral signatures for these signals. To this end, 450 bipolar EGMs from seven patients affected by post-ischaemic ventricular tachycardia were retrospectively annotated by an experienced cardiologist. Given the high variability of the morphologies observed, three different sub-classes of AVPs and two subcategories of post-ischaemic physiological potentials were considered. All signals were acquired by the CARTO\uae 3 system during substrate-guided catheter ablation procedures. Our findings indicated that the main frequency contributions of physiological and pathological post-ischaemic EGMs are found below 320 Hz. Statistical analyses showed that, when biases due to the signal amplitude influence are eliminated, not only physiological potentials show greater contributions below 20 Hz whereas AVPs demonstrate higher spectral contributions above~ 40 Hz, but several finer differences may be observed between the different AVP types

A novel simplified approach to radiofrequency catheter ablation of idiopathic ventricular outflow tract premature ventricular contractions : from substrate analysis to results

Summary: Premature ventricular contractions (PVCs) are a common finding in the general population. The most common site of PVCs, in patients without structural heart disease, is the right ventricular outflow tract (RVOT) and the left ventricular outflow tract (LVOT). The prognosis associated with frequent PVCs depends on the presence of structural heart disease, so that idiopathic PVCs have been considered benign. Recently however, evidence has emerged that a small percentage of those patients may present with polymorphic ventricular tachycardia or ventricular fibrillation or evolve to left ventricular dysfunction. Catheter ablation is indicated for frequent symptomatic PVCs refractory to medical therapy or in case of patient’s preference. Currently, catheter ablation is based on activation mapping, confirmed by pace mapping match of at least 11/12 ECG leads between the paced beat and the PVC morphology. The acute success rate ranges from 78% to 100% according to the series, and to the location of the PVCs. Remote magnetic navigation presents as a good option for PVC ablation offering a high success rate with better safety profile. Intraprocedural low PVC burden occurs in up to 30% to 48% of cases, resulting in either, cancelation of the ablation procedure in up to 11% of patients, or reduction of the success rate from 85% to 56% when ablation is attempted with pace mapping only. Recently non-invasive mapping systems based on the electrocardiogram analysis (ECGI) have been developed. These systems are capable of mapping an arrhythmia with just one beat, instead of the usual point by point acquisition, being especially useful in the case of rare arrhythmias. EGGI also constitutes a valuable noninvasive tool for studying the mechanisms of arrhythmias. With this system we were able to demonstrate the presence of an electrophysiological substrate in the RVOT of patients with PVCs and apparently normal hearts. It has been accepted for many years that in patients with idiopathic PVCs from the outflow tracts, the RVOT displays normal electroanatomical mapping features and electrophysiological properties. However, we have demonstrated that there is a substrate for idiopathic PVCs in the form of low voltage areas (LVAs) that are not detected by usual image methods including cardiac magnetic resonance (CMR). We described for the first time, the association between the presence of ST-segment elevation in V1-V2 at the 2nd intercostal space (ICS) with LVAs across the RVOT and have proposed it as a non-invasive electrocardiographic marker of LVAs. We also identified the presence of abnormal potentials in intracardiac electrograms at the ablation site during diastole, after the T wave of the surface ECG that became presystolic during the PVC and were called diastolic potentials (DPs). In Chapter V we describe in detail the study that validated those findings and evaluated the feasibility and efficacy of a proposed simplified substrate approach, for catheter ablation in patients with low intraprocedural PVC burden, defined as less than 2 PVCs/min in the first 5 minutes of the procedure. It consists of fast mapping of the RVOT in sinus rhythm looking for LVAs and DPs, identifying the area, and finally performing a restricted activation map of the PVCs at that area. Briefly, it was a prospective single-arm clinical trial at two centers and three groups were studied: a) patients with low intraprocedural PVC burden that underwent ablation with the novel simplified approach method (study group); b) patients with low intraprocedural PVC burden that underwent ablation using the standard activation mapping method between 2016 and 2018 (historical group); and c) patients without PVCs, subjected to catheter ablation of supraventricular tachycardias that agreed to have a voltage map of the RVOT in sinus rhythm performed (validation group). The calculated sample size was 38 patients in each group. The exclusion criteria were as follows: known structural heart disease, history of sustained ventricular arrhythmias, inability to perform CMR, previous ablation and standard 12-Lead ECG with evidence of conduction or electrical disease or abnormal QRS morphology were excluded. Patients in the study and validation groups, had an ECG performed at the 2nd ICS and the RVOT mapped in sinus rhythm to assess the presence of ST-segment elevation, and LVAS and DPs, respectively. The results were compared between both groups. The study group and the historical group were compared regarding the efficacy of the new simplified ablation method in terms of abolishment of the PVCs and improvement of procedure speed and success rate. When available, ECGI was performed in the study group to evaluate the accuracy of the method to identify the site of origin of the PVCs. The ECGI was performed with two systems, the Amycard (EP Solutions SA, Switzerland) and the VIVO (Catheter Precision, NJ USA). The prevalence of LVAs and DPs was significantly higher in the study group in comparison with the validation group, respectively, 71% vs 11%, p<0.0001 and 87% vs 8%, p<0.0001. The ST-segment elevation was a good predictor of LVAS with a sensitivity of 87%, specificity of 96%, positive predictor value of 93% and negative predictor value of 91%. The novel simplified approach abolished the PVCs in 90% of the patients as opposed to 47% of patients in the historical group, p<0.0001. Only 74% patients underwent ablation in the historical group versus 100% in the study group. In patients that underwent ablation, the procedure time was significantly lower in the study group when comparing to the historical group, 130 (100-164) vs 183 (160-203) min, p<0.0001 and the success rate was significantly higher, 90% vs 64%, p=0.013. The recurrence rate in patients with a successful ablation after a median follow-up time of 1060 (574-1807) days, was not significantly different between both groups, Log-Rank=0.125 ECGI before ablation was performed in 17 patients in the study group. In 6 patients the ECGI was performed just with the Amycard system, in two just with the VIVO system and in 9 patients both systems were used. We found a good agreement between the ECGI and the invasive mapping, with the predicted site of origin being in the same or contiguous segment of the ablation site in 14/15 patients (93%) with the Amycard system and in 100% of patients with the VIVO system. When both systems were used simultaneously, the agreement between them was 8/9 (90%). So, in conclusion, the proposed approach partially based on substrate mapping including searching for LVAs and DPs, proved to be feasible, faster, and more efficient than the previous approach based exclusively on activation mapping. ST-segment elevation at the 2nd ICS proved to be a good predictor of LVAs. ECGI was a valuable tool to noninvasively predict the site of origin the arrhythmia

Modern mapping and ablation of idiopathic outflow tract ventricular arrhythmias

Outflow tract (OT) premature ventricular complexes (PVCs) are being recognized as a common and often troubling, clinical electrocardiographic finding. The OT areas consist of the Right Ventricular Outflow Tract (RVOT), the Left Ventricular Outflow Tract (LVOT), the Aortomitral Continuity (AMC), the aortic cusps and the Left Ventricular (LV) summit. By definition, all OT PVCs will exhibit an inferior QRS axis, defined as positive net forces in leads II, III and aVF. Activation mapping using the contemporary 3D mapping systems followed by pace mapping is the cornerstone strategy of every ablation procedure in these patients. In this mini review we discuss in brief all the modern mapping and ablation modalities for successful elimination of OT PVCs, along with the potential advantages and disadvantages of each ablation technique

Mechanisms of Atrial Arrhythmia: Investigations of the Neuro-Myogenic Interface in the Mouse

Arrhythmia mechanisms rely on multiple factors including structural (myogenic), nervous (neurogenic), and interrelated (the neuro-myogenic interface) factors. I hypothesized that due to this neuro-myogenic interface, the intrinsic cardiac autonomic nervous system (ICANS) is involved in most atrial arrhythmias. This thesis also provides a Threshold Model as a tool to assess the role of different physiological factors influencing arrhythmia. This model allows relative comparison and interpretation of the role of various factors influencing arrhythmogenesis. The mouse allows relatively simple manipulation of genes to determine their role in arrhythmia. This thesis determined what atrial arrhythmias are inducible in the mouse (in vivo) and how to systematically study those arrhythmias. I found that atrial tachycardia/fibrillation (AT/F) and junctional tachycardia (JT) are inducible in the mouse. AF and JT pose significant clinical challenges as many patients do not respond well to current interventions. Neurogenic AF relies on acetylcholine, while myogenic AF relies, in part on gap junctions formed by connexins (Cxs). The atria has muscarinic M2 and M3 receptors. The duration of M2R/M3R G protein signalling is regulated by GTP hydrolysis, a process accelerated by the regulators of G protein signalling (RGS). RGS2 deficient (RGS2-/-) mice had reduced refractory periods that were normalized with a selective M3R blocker (Darifenacin) and increased susceptibility to AT/F induction compared to littermates. For the first time, this showed a role of M3 and RGS in atrial arrhythmia. Cx40 deficient (Cx40-/-) mice were protected from carbachol induced AT/F, while Cx43 G60S mutant (Cx43G60S/+) mice, with an 80% reduction in phospho-Cx43 in the atria were highly susceptible to AT/F that was terminated by darifenacin. This shows a novel neurogenic component to what was previously described as myogenic arrhythmia. Another novel finding was that JT has a neurogenic component, resulting from inappropriate AV nodal pacemaker activation initiated by autonomics. Ivabradine hydrochloride, a selective pacemaker channel blocker, prevented JT and may be useful in patients with JT. In conclusion, this thesis has provided novel findings of the vital role of the neuro-myogenic interface in atrial arrhythmias and has provided the basis for future investigations of potential therapeutic options for patients

Arrhythmogenic Right Ventricular Cardiomyopathy: Prognostic Value of Electroanatomic Voltage Mapping

Background: Endocardial voltage mapping (EVM) identifies low-voltage right ventricular (RV) areas, which may represent the electroanatomic scar substrate of life-threatening tachyarrhythmias. We prospectively assessed the prognostic value of EVM in a consecutive series of patients with arrhythmogenic right ventricular cardiomyopathy (ARVC). Methods: We studied 69 consecutive ARVC patients [47 males; median age 35 years(28-45)] who underwent electrophysiological study and both bipolar and unipolar EVM. The extent of confluent bipolar (<1.5mV) and unipolar (<6.0mV) low-voltage electrograms was estimated using the CARTO-incorporated area calculation software. Results: Fifty-three patients (77%) showed ≥1 RV electroanatomic scars with an estimated burden of bipolar vs unipolar low-voltage areas of 24.8% (7.2-31.5) and 64.8% (39.8-95.3), respectively (P=0.009). In the remaining patients with normal bipolar-EVM (n=16;23%), the use of unipolar EVM unmasked ≥1 region of low-voltage electrogram affecting 26.2% (11.6-38.2) of RV wall. During a median follow-up of 41 (28-56) months, 19(27.5%) patients experienced arrhythmic events, such as sudden death (n=1), appropriate ICD interventions (n=7), or sustained ventricular tachycardia (n=11). Univariate predictors of arrhythmic outcome included previous cardiac arrest or syncope (HR=3.4; 95%CI:1.4-8.8; P=0.03) and extent of bipolar low-voltage areas (HR=1.7 per 5%; 95%CI=1.5-2; P<0.001), while the only independent predictor was the bipolar low-voltage electrogram burden (HR=1.6 per 5%; 95% CI:1.2-1.9; P<0.001). Patients with normal bipolar-EVM had an uneventful clinical course. Conclusions: The extent of bipolar RV endocardial low-voltage area was a powerful predictor of arrhythmic outcome in ARVC, independently of history and RV dilatation/dysfunction. A normal bipolar-EVM characterized a low-risk subgroup of ARVC patients

New Imaging Technologies To Characterize Arrhythmic Substrate

The cornerstone of the new imaging technologies to treat complex arrhythmias is the electroanatomic (EAM) mapping. It is based on tissue characterization and in particular on determination of low potential region and dense scar definition. Recently, the identification of fractionated isolated late potentials increased the specificity of the information derived from EAM. In addition, non-invasive tools and their integration with EAM, such as cardiac magnetic resonance imaging and computed tomography scanning, have been shown to be helpful to characterize the arrhythmic substrate and to guide the mapping and the ablation. Finally, intracardiac echocardiography, known to be useful for several practical uses in the setting of electrophysiological procedures, it has been also demonstrated to provide important informations about the anatomical substrate and may have potential to identify areas of scarred myocardium

Non-Invasive Electrocardiographic Mapping of Arrhythmia and Arrhythmogenic substrate in the Human Ventricle.

PhD Theses.The ablation of ventricular tachycardia often involves mapping when the arrhythmia is ongoing. This is often limited by haemodynamic instability. Non-invasive electrocardiographic mapping (ECGI) may aid in the mapping process by allowing expedient localisation. However, insufficient testing of this technology against ground truth data has been conducted. Furthermore, the system could have utility in detection of arrhythmogenic substrate. Current clinical practice uses echocardiography to risk stratify patients for implantation of intracardiac defibrillators (ICDs). Invasive epicardial electrogram data was collected in 8 patients. Activation and repolarisation times were compared to ECGI derived data showing modest correlation. A detailed analysis of ventricular tachycardia sites of origin in the heart was elucidated using validated electrophysiological techniques. These were compared to ECGI derived data in 18 patients, showing better accuracy than the 12 lead ECG with a resolution of ~2.2cm suggesting it may be a useful adjunctive tool in mapping unstable VT. ECGI derived data collected during sinus rhythm was compared to invasive electrogram maps in 16 patients. The capacity of ECGI to localise scar showed modest accuracy. ECGI and Cardiac MRI scans were performed in 21 patients with cardiac amyloidosis. ECGI showed cardiac amyloidosis to be associated with both ventricular conduction and repolarization abnormalities, supporting the hypothesis that arrhythmic mechanisms may be linked to mortality in this condition

Atrial conduction velocity mapping: clinical tools, algorithms and approaches for understanding the arrhythmogenic substrate

Characterizing patient-specific atrial conduction properties is important for understanding arrhythmia drivers, for predicting potential arrhythmia pathways, and for personalising treatment approaches. One metric that characterizes the health of the myocardial substrate is atrial conduction velocity, which describes the speed and direction of propagation of the electrical wavefront through the myocardium. Atrial conduction velocity mapping algorithms are under continuous development in research laboratories and in industry. In this review article, we give a broad overview of different categories of currently published methods for calculating CV, and give insight into their different advantages and disadvantages overall. We classify techniques into local, global, and inverse methods, and discuss these techniques with respect to their faithfulness to the biophysics, incorporation of uncertainty quantification, and their ability to take account of the atrial manifold

Multichannel Analysis of Intracardiac Electrograms - Supporting Diagnosis and Treatment of Cardiac Arrhythmias

Cardiologists diagnose and treat atrial tachycardias using electroanatomical mapping systems. These can be combined with multipolar catheters to record intracardiac electrograms. Within this thesis, various signal processing techniques were implemented and benchmarked to analyze electrograms. They support the physician in diagnosis and treatment of atrial flutter and atrial fibrillation. The developed methods were assessed using simulated data and demonstrated on clinical cases