Scar Border Research Articles

A Core of Keratocan-Negative Cells Survives in Old Corneal Scars

Corneal scars originate from keratocyte-derived fibroblasts and myofibroblasts that are ultimately cleared through apoptosis or revert to keratocytes. A mouse model expressing the keratocyte lineage-specific reporter KeraRT/tetO-Cre/mTmG (I-KeramTmG) was interrogated to elucidate cell phenotype dynamics during scar maturation. This model expresses tdTomato (red) in all keratocan-negative cells, while enhanced green fluorescent protein (green) is expressed only by keratocytes. A 1-mm full-thickness keratotomy was generated in adult I-KeramTmG mice. The presence of keratocytes was determined at 3, 6, and 10 months after injury. At 3 and 6 months, few green cells were visualized at the scar borders, while few or no green cells were seen in the central (core) scar. At 10 months, green cells were seen throughout the scar, but most cells were red. Proliferation of stromal cells after injury was studied by 5-ethynyl-2'-deoxyuridine labeling and Ki-67 staining; both assays showed proliferation only during the first 2 weeks after injury. Second harmonic generation microscopy showed thickened and irregularly arranged collagen fibers in scars, suggesting that neither extracellular matrix organization nor cell phenotype had changed significantly at 10 months after injury. Findings from invivo experiments suggest that in old corneal scars, a nonkeratocyte phenotype persists in an abnormal matrix with unique characteristics that probably prevent the regression of fibroblasts and myofibroblasts to keratocytes or invasion of surrounding keratocytes.

Olfactory ensheathing cells from adult female rats are hybrid glia that promote neural repair.

Olfactory ensheathing cells (OECs) are unique glial cells found in both central and peripheral nervous systems where they support continuous axonal outgrowth of olfactory sensory neurons to their targets. Previously we reported that following severe spinal cord injury, OECs transplanted near the injury site modify the inhibitory glial scar and facilitate axon regeneration past the scar border and into the lesion. To better understand the mechanisms underlying the reparative properties of OECs, we used single-cell RNA-sequencing of OECs from adult rats to study their gene expression programs. Our analyses revealed five diverse OEC subtypes, each expressing novel marker genes and pathways indicative of progenitor, axonal regeneration, secreted molecules, or microglia-like functions. We found substantial overlap of OEC genes with those of Schwann cells, but also with microglia, astrocytes, and oligodendrocytes. We confirmed established markers on cultured OECs, and localized select top genes of OEC subtypes in olfactory bulb tissue. We also show that OECs secrete Reelin and Connective tissue growth factor, extracellular matrix molecules which are important for neural repair and axonal outgrowth. Our results support that OECs are a unique hybrid glia, some with progenitor characteristics, and that their gene expression patterns indicate functions related to wound healing, injury repair and axonal regeneration.

Abstract Mo073: Elucidating the Role of Cardiac Radiotherapy on the Sympathetic Nervous System as a Treatment for Ventricular Tachycardia

Ventricular tachycardia (VT) is a dangerous arrhythmia that occurs in structurally and electrically heterogenous regions of the diseased heart, leading to sudden cardiac arrest and death if left untreated. One of the main drivers underlying the arrhythmogenic substrate is abnormal remodeling of the autonomic nervous system after cardiac injury, resulting in a heterogenous distribution of sympathetic innervation and subsequent ventricular arrhythmia. In patients with VT refractory to conventional therapy, noninvasive cardiac stereotactic body radiotherapy (SBRT) has emerged as a promising new treatment. Here, we investigated whether cardiac radiotherapy homogenizes the arrhythmogenic substrate through induction of cardiac sympathetic nerve innervation and activity in a closed-chest ischemia reperfusion murine model of ischemic heart failure. Using single nucleus-RNA sequencing, we identified global transcriptomic changes in the left ventricle 6 weeks after 25 Gray (Gy) cardiac X-ray radiation. Notably, these changes included increased expression of neurotrophins such as brain derived neurotrophic factor, a growth factor essential for neuronal survival and development, in irradiated hearts compared to sham controls. Consequently, Western blot and immunofluorescence showed increased expression of the sympathetic neuronal markers tyrosine hydroxylase and neuropeptide Y at the scar border zone of irradiated mice. Similar immunofluorescence results were observed at the irradiated border zone from the explanted heart of a patient previously targeted with 25 Gy compared to a nontargeted remote region within the same heart. These findings suggest a novel role for radiation-induced remodeling of the sympathetic nervous system in the anti-arrhythmic response to SBRT.

The importance of scar border zone size in VT presentation and recurrence in post MI patients

Abstract Introduction Available mapping data in post-myocardial infarction patients describe ventricular tachycardia (VT) re-entry circuit characteristics of slow VT, that are typically related to transmural scars. Fast VTs with cycle lengths close to the refractory period may be related to functional re-entry in the scar border zone. Functional re-entry related border zone VTs may be difficult to control by ablation. Purpose The aims of this study are (1) to describe electroanatomical voltage map (EAVM) characteristics in post myocardial infarction (MI) patients with spontaneous and inducible fast VTs and (2) to assess the relation between scar border zone size and ablation outcomes. Methods Consecutive post-MI patients undergoing VT ablation at a tertiary referral center from January 2012 to November 2018 were included. Fast VT was defined as a VT cycle length (VTCL) = ventricular refractory period + max. 30ms. Areas of scar border zone (using 0.5 – 2.1mV/3.0mV cut-offs (according to LV remodeling stage; LVEF<47% and LV end-systolic volume index of >50 ml/m2)) were measured on the EAVM and correlated with clinical outcomes. Results In total, 138 patients were included (86% male; left ventricular ejection fraction 35±10%; 86% remodeled LV). Twenty-three patients (17%) had ≥1 fast VT (mean VTCL 275±52ms) at presentation, mean VTCL of the remaining patients 397±88ms). The median scar border zone size was 27% [IQR 20-38] of the left ventricular endocardial surface. Patients who presented with a spontaneous fast VT had a larger border zone than patients with slower VT (32% [IQR 28 – 41] vs. 25% [IQR 16 – 36], p=0.01). After ablation, 79 (57%) patients remained inducible for any VT, including 59/79 (75%) for a fast VT (median VTCL fast VT 260ms [IQR 236 -280]). Patients who remained inducible for fast VTs had a larger border zone than patients who remained inducible for slower VTs (35% [IQR 27 – 44] vs. 26% [IQR 20 – 36], p<0.001). During a median follow-up of 26 months [IQR 8 – 47], 45 patients (33%) had a VT recurrence (mean VTCL 357±98ms). Patients with a below median (27%) scar border zone area had a lower VT recurrence rate compared to patients with an above median scar border zone area (recurrence rate: 16/66 (24%) vs. 29/72 (40%), p=0.03). Kaplan-Meier survival analysis showed better free VT survival in the below median border zone patients (Log-rank: p<0.05) (Figure 1). Conclusion Patients who present with spontaneous fast VTs or who remain inducible for fast VTs after ablation have larger scar border zones during EAVM compared to patients with presenting or remaining slower VTs. A larger border zone appeared to be associated with higher VT-recurrence rates. The scar border zone may play an important role as VT substrate for (fast) VTs and may not be easily targeted by current ablation techniques.VT-free survival stratified by median BZ

The effect of cardiosphere-derived cell extracellular vesicles embedded in cardiac matrix hydrogel on cardiac remodeling in a porcine model of ischemic cardiomyopathy

Abstract Background Numerous preclinical studies have confirmed that stem cell-derived extracellular vesicles (EVs) can prevent from negative cardiac remodeling after an ischemic injury, reduce the scar and preserve heart function. It is believed that by increasing the engraftment of the therapeutic product at the target site may bust its efficacy. The use of bioengineering materials such as hydrogels as delivery scaffolds for intramyocardial EVs administration may constitute a minimally invasive therapeutic strategy that improves the efficacy of EVs by increasing their permanence in the tissue. Objective To evaluate the therapeutic efficacy of a new regenerative product constituted by the combination of EVs secreted by cardiosphere-derived cell (CDC-EVs) embedded in a hydrogel-based scaffold made from decellularized cardiac matrix (HDM). Methods Twelve pigs (50% females) with induced ischemic cardiomyopathy were randomly assigned to receive: phosphate-buffer saline (PBS) as control group (n=4), CDC-EVs alone (n=4) and combination of CDC-EVs and HDM (EV-HDM, n=4). Treatment was administered via percutaneous intramyocardial injection in the scar border zone 1-month after myocardial infarction with NOGA system. Animals were followed-up another month and sacrificed. Hearts were excised for histological analysis performed according to the cardiac area: scar (anterior wall), scar border zone and remote zone (inferior wall). Functional evaluation was performed with cardiac magnetic resonance imaging immediately before- and 1-month after treatment. Results Cardiomyocytes size was significantly lower in EV-HDM group compared to control PBS both at scar border (4660± 2088 vs. 5254±2294 pixels; p=0.02) and remote areas (3381±1259 vs. 4237±1256 pixels; p<0.001), while no changes were observed in CDC-EV alone group compared to controls. Interstitial fibrosis was significantly lower in EV-HDM group compared to PBS controls both at scar epicardial side (34% vs. 44%; p=0.01) and remote areas (16% vs. 20%; p<0.01), similarly to CDC-EV vs. PBS (34% at the scar; p<0.01 and 17% at the remote zone; p=0.01). While left ventricular ejection fraction (LVEF) tended to decrease in PBS group from 36% to 32%, it showed an opposite trend in CDC-EV (from 35 % to 38%) and EV-HDM (from 31% to 37%). Conclusion The combined product of EV-HDM reduce cardiac fibrosis and hypertrophy, favorably affecting the remodeling process and may thus increase LVEF in ischemic heart disease. The results of our study fail to clearly demonstrate the superiority of EV-HDM over CDC-EVs alone, although it may exist.

Effects of Mesenchymal Stem Cell Injection into Healed Myocardial Infarction Scar Border Zone on the Risk of Ventricular Tachycardia.

The scar border zone is a main source of reentry responsible for ischemic ventricular tachycardia (VT). We evaluated the effects of mesenchymal stem cell (MSC) injection into the scar border zone on arrhythmic risks in a post-myocardial infarction (MI) animal model. Rabbit MI models were generated by left descending coronary artery ligation. Surviving rabbits after 4 weeks underwent left thoracotomy and autologous MSCs or phosphate-buffered saline (PBS) was administered to scar border zones in two rabbits in each group. Another rabbit without MI underwent a sham procedure (control). An implantable loop recorder (ILR) was implanted in the left chest wall in all animals. Four weeks after cell injections, ventricular fibrillation was induced in 1/2 rabbit in the PBS group by electrophysiologic study, and no ventricular arrhythmia was induced in the MSC group or control. Spontaneous VT was not detected during ILR analysis in any animal for 4 weeks. Histologic examination showed restoration of connexin 43 (Cx43) expression in the MSC group, which was higher than in the PBS group and comparable to the control. In conclusion, MSC injections into the MI scar border zone did not increase the risk of VT and were associated with favorable Cx43 expression and arrangement.

Comprehensive treatment of ear keloid: A case report

Ear keloid is one of the more common forms of keloid, which may cause pain and itching, and is aesthetically unappealing. Recurrence is common with any monotherapy which prompted a comprehensive, multidimensional approach. A 24-year-old female was evaluated in our department on April 6, 2021, due to an "8-year recurrence following a left ear keloid resection." In July 2013, a left auricle keloid excision was performed in a local hospital. One year following the operation, the scar at the surgical site had proliferated, gradually spreading beyond the original scar borders. Patients worry about recurrence after surgery affecting the appearance of the ear. Ear keloid. The patient underwent a 2-stage re-resection of the keloid, followed by postoperative radiotherapy, and triamcinolone acetonide injection around the incision at the time of the second operation. Finally, silicone gel was applied for antiscar treatment. There has been no postoperative recurrence of ear keloid during the 12-month follow-up. For ear keloids, combination therapy offers an improved approach with an excellent aesthetic appearance and less risk of recurrence than traditional monotherapy.

Current Advancements in Spinal Cord Injury Research-Glial Scar Formation and Neural Regeneration.

Spinal cord injury (SCI) is a complex tissue injury resulting in permanent and degenerating damage to the central nervous system (CNS). Detrimental cellular processes occur after SCI, including axonal degeneration, neuronal loss, neuroinflammation, reactive gliosis, and scar formation. The glial scar border forms to segregate the neural lesion and isolate spreading inflammation, reactive oxygen species, and excitotoxicity at the injury epicenter to preserve surrounding healthy tissue. The scar border is a physicochemical barrier composed of elongated astrocytes, fibroblasts, and microglia secreting chondroitin sulfate proteoglycans, collogen, and the dense extra-cellular matrix. While this physiological response preserves viable neural tissue, it is also detrimental to regeneration. To overcome negative outcomes associated with scar formation, therapeutic strategies have been developed: the prevention of scar formation, the resolution of the developed scar, cell transplantation into the lesion, and endogenous cell reprogramming. This review focuses on cellular/molecular aspects of glial scar formation, and discusses advantages and disadvantages of strategies to promote regeneration after SCI.

In vivo pulsed-field ablation in healthy vs. chronically infarcted ventricular myocardium: biophysical and histologic characterization.

Data on ventricular pulsed-field ablation (PFA) are sparse in the setting of chronic myocardial infarction (MI). The objective of this study was to compare the biophysical and histopathologic characteristics of PFA in healthy and MI swine ventricular myocardium. Myocardial infarction swine (n = 8) underwent coronary balloon occlusion and survived for 30 days. We then performed endocardial unipolar, biphasic PFA of the MI border zone and a dense scar with electroanatomic mapping and using an irrigated contact force (CF)-sensing catheter with the CENTAURI System (Galaxy Medical). Lesion and biophysical characteristics were compared with three controls: MI swine undergoing thermal ablation, MI swine undergoing no ablation, and healthy swine undergoing similar PFA applications that included linear lesion sets. Tissues were systematically assessed by gross pathology utilizing 2,3,5-triphenyl-2H-tetrazolium chloride staining and histologically with haematoxylin and eosin and trichrome. Pulsed-field ablation in healthy myocardium generated well-demarcated ellipsoid lesions (7.2 ± 2.1 mm depth) with contraction band necrosis and myocytolysis. Pulsed-field ablation in MI demonstrated slightly smaller lesions (depth 5.3 ± 1.9 mm, P = 0.0002), and lesions infiltrated into the irregular scar border, resulting in contraction band necrosis and myocytolysis of surviving myocytes and extending to the epicardial border of the scar. Coagulative necrosis was present in 75% of thermal ablation controls but only in 16% of PFA lesions. Linear PFA resulted in contiguous linear lesions with no gaps in gross pathology. Neither CF nor local R-wave amplitude reduction correlated with lesion size. Pulsed-field ablation of a heterogeneous chronic MI scar effectively ablates surviving myocytes within and beyond the scar, demonstrating promise for the clinical ablation of scar-mediated ventricular arrhythmias.

Fragmented QRS on 12-lead electrocardiogram predicts long-term prognosis in patients with cardiac sarcoidosis.

Fragmented QRS (fQRS) on a 12-lead electrocardiogram is a known marker of fatal arrhythmias or cardiac adverse events in ischemic and non-ischemic cardiomyopathy patients. Nonetheless, the association between fQRS and clinical outcomes in patients with cardiac sarcoidosis (CS) remains unclear. Herein, we investigated whether fQRS is associated with long-term clinical outcomes in CS patients. A total of 78 patients who received immunosuppressive therapy (IST) for clinically diagnosed CS were retrospectively examined. Patients were classified into two groups according to the presence (n = 19) or absence (n = 59) of fQRS on electrocardiogram before IST. The primary outcome was the composite event of all-cause death, ventricular tachyarrhythmias (VTs), and hospitalization for heart failure. Results of late gadolinium enhancement on cardiac magnetic resonance imaging were also analyzed. During a median follow-up period of 3.7years (interquartile range: 1.6-6.2years), the primary outcome occurred more frequently in patients with fQRS than in those without (47% vs. 13%, log-rank p = 0.002). Multivariable Cox regression analyses showed that fQRS was an independent determinant of the primary outcome. The incidence of VTs, within 12months of IST initiation, was comparable between the two groups; however, late-onset VTs, defined as those occurring ≥ 12months after IST initiation, occurred more frequently in the fQRS group (21% vs. 2%, log-rank p = 0.002). The scar zone and scar border zone were greater in patients with fQRS than in those without it. In conclusion, our analysis suggests that fQRS is an independent predictor of adverse events, particularly late-onset VTs, in patients with CS.

Assessing the arrhythmogenic risk of engineered heart tissue patches through in silico application on infarcted ventricle models

BackgroundPost myocardial infarction (MI) ventricles contain fibrotic tissue and may have disrupted electrical properties, both of which predispose to an increased risk of life-threatening arrhythmias. Application of epicardial patches obtained from human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are a potential long-term therapy to treat heart failure resulting from post MI remodelling. However, whether the introduction of these patches is anti- or pro-arrhythmic has not been studied. MethodsWe studied arrhythmic risk using in silico engineered heart tissue (EHT) patch engraftment on human post-MI ventricular models. Two patient models were studied, including one with a large dense scar and one with an apparent channel of preserved viability bordered on both sides by scar. In each heart model a virtual EHT patch was introduced as a layer of viable tissue overlying the scarred area, with hiPSC-CMs electrophysiological properties. The incidence of re-entrant and sustained activation in simulations with and without EHT patches was assessed and the arrhythmia inducibility compared in the context of different EHT patch properties (conduction velocity (CV) and action potential duration (APD)). The impact of the EHT patch on the likelihood of focal ectopic impulse propagation was estimated by assessing the minimum stimulus strength and duration required to generate a propagating impulse in the scar border zone (BZ) with and without patch. ResultsWe uncovered two main mechanisms by which ventricular tachycardia (VT) risk could be either augmented or attenuated by the interaction of the patch with the tissue. In the case of isthmus-related VT, our simulations predict that EHT patches can prevent the induction of VT when the, generally longer, hiPSC-CMs APD is reduced towards more physiological values. In the case of large dense scar, we found that, an EHT patch with CV similar to the host myocardium does not promote VT, while EHT patches with lower CV increase the risk of VT, by promoting both non-sustained and sustained re-entry. Finally, our simulations indicate that electrically coupled EHT patches reduce the likelihood of propagation of focal ectopic impulses. ConclusionsThe introduction of EHT patches as a treatment for heart failure has the potential to augment or attenuate the risk of ventricular arrhythmias, and variations in the anatomic configuration of the substrate, the functional properties of the BZ and the electrophysiologic properties of the patch itself will determine the overall impact. Planning for delivery of this therapy will need to consider the possible impact on arrhythmia.

Lesion Extension and Neuronal Loss after Spinal Cord Injury Using X-Ray Phase-Contrast Tomography in Mice.

Following spinal cord injury (SCI) the degree of functional (motor, autonomous, or sensory) loss correlates with the severity of nervous tissue damage. An imaging technique able to capture non-invasively and simultaneously the complex mechanisms of neuronal loss, vascular damage, and peri-lesional tissue reorganization is currently lacking in experimental SCI studies. Synchrotron X-ray phase-contrast tomography (SXPCT) has emerged as a non-destructive three-dimensional (3D) neuroimaging technique with high contrast and spatial resolution. In this framework, we developed a multi-modal approach combining SXPCT, histology and correlative methods to study neurovascular architecture in normal and spinal level C4-contused mouse spinal cords (C57BL/6J mice, age 2-3 months). The evolution of SCI lesion was imaged at the cell resolution level during the acute (30 min) and subacute (7 day) phases. Spared motor neurons (MNs) were segmented and quantified in different volumes localized at and away from the epicenter. SXPCT was able to capture neuronal loss and blood-brain barrier breakdown following SCI. Three-dimensional quantification based on SXPCT acquisitions showed no additional MN loss between 30 min and 7 days post-SCI. In addition, the analysis of hemorrhagic (at 30 min) and lesion (at 7 days) volumes revealed a high similarity in size, suggesting no extension of tissue degeneration between early and later time-points. Moreover, glial scar borders were unevenly distributed, with rostral edges being the most extended. In conclusion, SXPCT capability to image at high resolution cellular changes in 3D enables the understanding of the relationship between hemorrhagic events and nervous structure damage in SCI.

The derivative of tissue activation as a marker of arrhythmogenic myocardium

Mapping techniques to identify diseased myocardial substrate during ventricular tachycardia ablation procedures remain limited. We hypothesized that tissue derivative of the voltage with respect to time (dV/dt), the slope of the unipolar ventricular electrogram registered by local ventricular activation, represents a unique parameter for identifying potential arrhythmogenic tissue in the ischemic scar border zone. Using high-resolution electrical mapping, we examined dV/dt characteristics in the border zone of animals after chronic myocardial infarction (MI). Minimum dV/dt (dV/dtmin) in MI animals was less than that in control animals (-344.7 ± 68.7 in controls vs -174.2 ± 104.5 in MI; P < .001) and related to ventricular fibrosis. In MI animals, dV/dtmin values were divided into high (≤-200 μV/ms) and low (>-200 μV/ms) dV/dtmin. Low dV/dtmin regions harbored arrhythmogenic substrates that were characterized by (1) high responsiveness to sympathetic stimulation, (2) presence of late potentials, and (3) lower unipolar and bipolar voltage amplitudes. Our data indicate that dV/dtmin is a unique parameter for identifying arrhythmogenic myocardium and may add a useful metric to conventional mapping strategies.

Sinus rhythm endocardial mapping for channels identification in ischemic ventricular tachycardia using a modified electrophysiological triad

Abstract Background In a previous study it was demonstrated that an electrophysiological triad was able to identify critical isthmus in atrial flutter (AFL) patients. This triad is based in the Carto® electroanatomical mapping (EAM) version 7, which displays a histogram of the local activation times (LAT) of the tachycardia cycle length (TCL), in addition to the activation and voltage maps. Purpose This study aimed to prospectively assess the ability of a modified electrophysiological triad to identify and localize the ventricular tachycardia's (VT) channels and entrance zones during sinus rhythm mapping. Methods Prospective analysis of a unicentric registry of individuals who underwent ischemic VT ablation with Carto® EAM, all in sinus rhythm. All patients with non-ischemic etiology, lack of high-density EAM or lack of mapping in any of the left ventricle walls or structures were excluded. Areas of late potentials and possible channels of re-entry were compared to a modified electrophysiological triad constituted by: areas of low-voltage (&amp;lt;0.5mV), a site of deep histogram valley (LAT-Valley) with less than 20% density points relative to the highest density zone and a prolonged LAT-Valley duration that included 10% or more of the total activation time mapped. We also assessed the relationship between the pre-valley bar (the LAT histogram bar immediately before the prolonged LAT-Valley) and the channel entrances. Results A total of 14 patients (14 men, median age 70 IQR 64–78 years) were included. All patients presented with ischemic VT and 86% had a previous inferior myocardial infarction. The median number of collected points were 1733 (IQR 1363–2729). All sinus rhythm maps presented with at least 1 LAT-Valley in the analysed histograms. All arrhythmias were effectively treated after undergoing radiofrequency in the LAT-Valley location, either by blocking the channel entrances or scar homogenization ablation strategy. Also, the pre-valley bar in the histogram marked all the channel entrances in the scar borders. No patient had relapse after a clinical follow up of over 6 months. Conclusion In a prospective analysis, a modified electrophysiological triad was able to identify the scar channels in sinus rhythm in all patients. The pre-valley bar in the histogram disclosed the channel entrances. Further studies are needed to assess the usefulness of this algorithm to simplify catheter ablation and improve clinical outcomes. Funding Acknowledgement Type of funding sources: None.

Sinus rhythm endocardial mapping for channels identification in ischemic ventricular tachycardia using a modified electrophysiological triad

Abstract Funding Acknowledgements Type of funding sources: None. Background In a previous study it was demonstrated that an electrophysiological triad was able to identify critical isthmus in atrial flutter (AFL) patients. This triad is based in the Carto® electroanatomical mapping (EAM) version 7, which displays a histogram of the local activation times (LAT) of the tachycardia cycle length (TCL), in addition to the activation and voltage maps. Purpose This study aimed to prospectively assess the ability of a modified electrophysiological triad to identify and localize the ventricular tachycardia’s (VT) channels and entrance zones during sinus rhythm mapping. Methods Prospective analysis of a unicentric registry of individuals who underwent ischemic VT ablation with Carto® EAM, all in sinus rhythm. All patients with non-ischemic etiology, lack of high-density EAM or lack of mapping in any of the left ventricle walls or structures were excluded. Areas of late potentials and possible channels of re-entry were compared to a modified electrophysiological triad constituted by: areas of low-voltage (&amp;lt;0.5mV), a site of deep histogram valley (LAT-Valley) with less than 20% density points relative to the highest density zone and a prolonged LAT-Valley duration that included 10% or more of the total activation time mapped. We also assessed the relationship between the pre-valley bar (the LAT histogram bar immediately before the prolonged LAT-Valley) and the channel entrances. Results A total of 14 patients (14 men, median age 70 IQR 64-78 years) were included. All patients presented with ischemic VT and 86% had a previous inferior myocardial infarction. The median number of collected points were 1733 (IQR 1363─2729). All sinus rhythm maps presented with at least 1 LAT-Valley in the analysed histograms. All arrhythmias were effectively treated after undergoing radiofrequency in the LAT-Valley location, either by blocking the channel entrances or scar homogenization ablation strategy. Also, the pre-valley bar in the histogram marked all the channel entrances in the scar borders. No patient had relapse after a clinical follow up of over 6 months. Conclusion In a prospective analysis, a modified electrophysiological triad was able to identify the scar channels in sinus rhythm in all patients. The pre-valley bar in the histogram disclosed the channel entrances. Further studies are needed to assess the usefulness of this algorithm to simplify catheter ablation and improve clinical outcomes.

Adrenergic stimulation amplifies the difference in beat-to-beat variability between the scar border zone and remote region

Abstract Funding Acknowledgements Type of funding sources: Public Institution(s). Main funding source(s): KU Leuven BOF-C1 “Blood pressure induced premature ventricular beats as triggers for ventricular arrhythmia in ischemic cardiomyopathy” Background Myocardial infarction (MI) results in a dense scar region surrounded by a heterogeneous region of fibrosis and remodeled myocytes called the border zone (BZ). Beta-adrenergic stimulation results in increased beat-to-beat variability of repolarization (BVR) which could increase spatial heterogeneity and arrhythmia vulnerability. Objective To examine the effect of adrenergic stimulation on the beat-to-beat variability in the BZ, compared to the remote region, using novel methodology for determining spatially dense activation-repolarization intervals. Methods Anterior-septal myocardial infarction (MI) was induced in 10 domestic pigs by 120-minute occlusion of the left anterior descending artery followed by reperfusion. Electro-anatomical mapping was performed after one month. The BZ was defined using contact mapping as the region with bipolar voltage between 0.5 and1.5mV. A non-contact recording of a 64-electrode array was translated to 2048 non-contact electrograms distributed over the LV (EnSite PrecisionTM, St. Jude/Abbott Medical). Electrophysiological recordings were made during baseline and during an isoproterenol (ISO) infusion (incremental doses of 0.01µg/kg until 0.04µg/kg). In each of the 2048 points non-contact electrograms over 25 consecutive beats were processed to determine the BVR using a custom-made algorithm, validated against monophasic action potential recordings. Results During baseline conditions the maximal BVR was increased in the BZ compared to the remote region (BZ: 3.28±0.90 ms vs remote: 2.61±0.67 ms, P=0.002). During ISO infusion the maximal BVR was also increased in the BZ (BZ: 3.55±0.74 ms vs remote: 2.21±0.60 ms, P&amp;lt;0.001). During baseline the BZ exhibited a larger spatial variance of BVR than the remote region (BZ: 0.20±0.11 ms2 vs remote: 0.087±0.055 ms2, P=0.002). During ISO infusion the spatial variance of BVR was larger in the BZ (BZ: 0.23±0.12 ms2 vs remote: 0.083±0.056 ms2, P=0.001). The maximal BVR was not significantly different during baseline and ISO in the BZ, nor the remote region (P&amp;gt;0.05). However, the difference of the maximal BVR between BZ and remote regions was significantly increased during ISO (baseline: 0.67±0.48 ms vs ISO: 1.34±0.49ms, P=0.001). Conclusion The MI BZ showed increased temporal heterogeneity in repolarization that could serve as functional substrate for re-entry. Adrenergic stimulation amplified this vulnerability by increasing the difference in maximal BVR between BZ and remote regions.

Noncontact whole-chamber charge density mapping of the left ventricle: Preclinical evaluation in a sheep model.

Conventional contact-based electroanatomic mapping is poorly suited for rapid or dynamic ventricular arrhythmias. Whole-chamber charge density (CD) mapping could efficiently characterize complex ventricular tachyarrhythmias and yield insights into their underlying mechanisms. The purpose of this study was to evaluate the feasibility and accuracy of noncontact whole-chamber left ventricular (LV) CD mapping and to characterize CD activation patterns during sinus rhythm, ventricular pacing, and ventricular fibrillation (VF). Ischemic scar as defined by CD amplitude thresholds was compared to late gadolinium enhancement criteria on magnetic resonance imaging using an iterative closest point algorithm. Electrograms recorded at sites of tissue contact were compared to the nearest noncontact CD-derived electrograms to calculate signal morphology cross-correlations and time differences. Regions of consistently slow conduction were examined relative to areas of scar and to localized irregular activation (LIA) during VF. Areas under receiver operating characteristic curves (AUCs) of CD-defined dense and total LV scar were 0.92 ± 0.03 and 0.87 ± 0.06, with accuracies of 0.86 ± 0.03 and 0.80 ± 0.05, respectively. Morphology cross-correlation between 8677 contact and corresponding noncontact electrograms was 0.93 ± 0.10, with a mean time difference of 2.5 ± 5.6 ms. Areas of consistently slow conduction tended to occur at scar borders and exhibited spatial agreement with LIA during VF (AUC 0.90 ± 0.02). Noncontact LV CD mapping can accurately delineate ischemic scar. CD-derived ventricular electrograms correlate strongly with conventional contact-based electrograms. Regions with consistently slow conduction are often at scar borders and tend to harbor LIA during VF.

CA-530-04 UTILITY OF ABLATION INDEX FOR GUIDING ABLATION IN VENTRICULAR TISSUE

Ablation index (AI) is a widely used variable incorporating power, time, and contact force for predicting lesion size for radiofrequency ablation (RFA). Its utility for guiding ablation in ventricular tissue, and particularly in clinically relevant scar tissue, has not been studied. To examine the utility and limitations of AI for predicting lesions dimensions in healthy and scarred ventricular tissue. This study included three steps: 1) In an ex-vivo bath model of fresh porcine hearts, RFA was performed using Thermocool STSF® (Biosense Webster) at a fixed power of 30W and an AI value range of 400-1200 at increments of 100; 2) In an in-vivo beating heart model of healthy porcine, RFA was performed at an AI value range of 500-900 at increments of 100; 3) in an in-vivo beating heart model of healed anterior wall infarction, RFA at an AI value range of 600-900 was performed at scar border zone defined by low voltage and abnormal electrograms. The relationship between AI and lesions dimensions was analyzed. In ex-vivo hearts, lesion width and depth had positive correlation with AI values (R=0.97, P<0.01; R=0.96, P<0.01, respectively). The relationship between lesion width and depth was linear between AI values of 400-900 (Width 1.4mm/100; Depth 0.9mm/100) but became flatter at 900-1200 (Width 0.05mm/100; Depth 0.28mm/100) as shown in Figure 1. In healthy beating ventricles, a similar positive correlation between AI values and lesions width and depth was observed (R=0.99, P<0.01; R=0.97, P<0.01, respectively) with 90% of lesion depth achieved at an AI value of 900. In contrast, AI did not correlate with lesion depth at infarcted myocardium (R=-0.23, P=0.74). Furthermore, lesion architecture was influenced by the spatial relationship between viable and scarred myocardium, with lesion growth-restricted predominantly to viable myocardium superficial to the infarct. Figure 2 shows gross pathological examples of lesions at variable AI values in healthy and scarred ventricular myocardium. In healthy ventricle, AI has a positive correlation to lesion dimensions with submaximal depth achieved at an AI value of 700. However, in scarred myocardium, AI has a poor correlation to lesion dimensions, with lesion growth restricted to viable myocardium superficial to the infarct.View Large Image Figure ViewerDownload Hi-res image Download (PPT)

Purkinje-related monomorphic ventricular tachycardia as a mechanism for electrical storm in ischemic heart disease

A 60-years-old male with remote anterior myocardial infarction (MI) was referred for catheter ablation of electrical storm related to monomorphic ventricular tachycardia (MVT). Radiofrequency applications targeting pre-systolic potentials abolished all clinical MVTs.Scar-associated Purkinje-related MVT mimicking fascicular VT is a rare mechanism of post-MI MVT. The surviving Purkinje cells within scar border zones, responsible for VF during acute MI, may also generate MVT after scar organization occurring with time or after VF ablation. Identification of this mechanism is useful as ablation of a limited area can rapidly eliminate several MVTs.

B-PO05-206 OMNIPOLAR MAPPING CLARIFIES AMBIGUOUS ATRIAL TACHYCARDIA ISOCHRONAL MAP IN PATIENT WITH TETRALOGY OF FALLOT

Atrial Tachycardia (AT) in adult congenital heart disease (ACHD) result from complex anatomy due to ACHD and surgical repair. Multiple scar areas harbor slow conduction, delayed activation and reentry circuits, limiting standard bipolar mapping of local activation time (LAT). New mapping technique utilizing orthogonal bipoles to construct electrograms (EGM) in 360 degrees, Omnipolar Mapping (OM), displays wavefront vector map as arrows utilizing 16 pole grid-like catheter (HD Grid), displayed as static map, or live map of grid OM as it moves throughout chamber, for real-time wavefront propagation display. N/A 43M repaired Tetralogy of Fallot underwent mapping and ablation for AT. LAT with Abbott Precision system and HD Grid showed large low voltage area (LVA) at lateral right atrium (RA). AT1 mapped to the superior scar border. Radiofrequency (RF) changed cycle length (CL) from 200ms to 240 ms. Remapping showed confusing LAT, with multiple “early” areas (Fig 1a). Adjusting mapping window displayed more focal origin (FO) (Fig 1b) on RA septum (AT2). RF here again slowed tachycardia to 315ms. Remapping showed AT3 was typical flutter. Offline analysis with research software allowed for OM. AT2 Static vector map showed FO “starburst” pattern (Fig 1a,b): arrows pointing outward from FO (successful RF, brown circle). “Real time” HD Grid vector map displayed this pattern at FO within first 6 minutes of mapping (Fig 1c). Vectors pointed away from FO when HD Grid positioned adjacent to the FO (Fig 1d). This difficult case illustrates HD Grid and OM may offer superior efficiency and less ambiguity for mapping of arrhythmias in complex substrates.