Scar Border Zone Research Articles

Abstract Mo037: Cardiac-Selective TRPV1 Afferent Ablation in Subacute Myocardial Infarction Ameliorates Adverse Remodeling and Ventricular Arrhythmogenesis

Background: Ventricular arrhythmias (VT/VF), the most common cause of sudden death after myocardial infarction (MI), can be ameliorated by cardiac-selective transient receptor potential cation channel subfamily V member 1 (TRPV1) afferent ablation at the time of infarction in animal models. To enable translation to human, it remains unknown whether afferent depletion in the subacute phase of MI will reduce arrhythmias and mitigate long-term structural remodeling. Objectives: To assess the role of cardiac-selective TRPV1 afferent ablation two weeks after MI on the long-term ventricular arrhythmogenesis and adverse structural remodeling. Methods: Yorkshire pigs were randomized to resiniferatoxin (RTX 5.0µg/ml: n=10) or vehicle(n=6) 14days after the left anterior descending artery infarct. Four weeks later, terminal experiments were conducted to evaluate the effect of RTX on cardiac structural and functional remodeling, ventricular arrhythmogenesis, and autonomic reflex function. Results: Cardiac afferent depletion via RTX administration was confirmed by diminished sympathetic response to TRPV1 agonists (bradykinin and capsaicin) and by immunohistochemical analysis of ventricular innervation. Compared to the vehicle treated group, the RTX administration reduced LV dimension (p<0.01), repolarization heterogeneity (p<0.01) and ventricular arrhythmogenesis (program stimulation; p=0.01 and CsCl induced PVCs;p<0.01). In the scar-border zone, myocytolysis and nerve sprouting, which are associated with VT/VF, were attenuated in the RTX group (abnormality score; p=0.01 and nerve sprouting index; p < 0.01). T cell infiltration in dorsal root ganglia was suppressed in the RTX group (p = 0.02). RNA-sequencing of stellate ganglia revealed downregulation of adrenergic genes tyrosine hydroxylase and neuropeptide-Y in the RTX group. Taken together, these results suggest that cardiac afferent ablation in subacute MI alleviates adverse structural remodeling and ventricular arrhythmogenesis by targeting neuroinflammation and reducing stellate ganglion sympathetic overexcitation. Conclusion: Cardiac TRPV1 afferent depletion in subacute MI is a promising disease altering treatment for patients suffering from MI.

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.

The importance of the right ventricular insertion area for the functional substrate of ventricular tachycardia after myocardial infarction

Abstract Funding Acknowledgements Type of funding sources: None. Background Conducting systematic annotation and ablation of evoked delayed potentials (EDP) in response to short coupled right ventricular extra-stimuli (RV-ES) has improved ablation outcome of post myocardial infarction (MI) ventricular tachycardia (VT). The reported short radiofrequency catheter ablation (RFCA) times suggests the presence of predilection areas for these functional substrates. Purpose To evaluate the electroanatomical characteristics and distribution of EDPs in post-MI patients referred for RFCA of VT. Methods Electroanatomical mapping (EAM) data of 48 post-MI patients (69 ± 9 years, 39 male, LV ejection fraction 36 ± 10%, anterior MI 20 [42%], inferior MI 28 [58%]), who underwent functional substrate mapping and ablation were analyzed. Pre-procedural cardiac CTs of 16 patients (8 anterior, 8 inferior MI) were integrated with EAM data. Infarct extension (defined as bipolar voltage [BV] <3.0mV, dense scar <0.5mV and scar borderzone [BZ] 0.5-3mV) and EDP location were determined based on the AHA 17-segment model of the left ventricle. Results RV-ES was performed during mapping at 2180 LV sites (median 46 per patient, range 8-81) and EDPs were observed at 631 (29%) sites. Patients had a median of 11 (range 1-37) EDP sites. Compared to no-EDP sites, EDP sites had lower BV (median 0.57 mV vs. 0.77 mV, P <0.001), longer duration (median 79 ms vs. 66 ms, P <0.001), and larger number of positive sharp deflections (median 6 vs. 5, P <0.001) during sinus rhythm. Of all EDP sites, 278 (44%), 286 (45%), 64 (10%), and 3 (1%) had BV of <0.5mV, ≥ 0.5mV and <1.5 mV, a BV of ≥1.5 mV and <3.0 mV, and a BV of >3.0 mV, respectively. In the 16 patients with CT image integration, a total of 124/272 segments showed EA scar with a median (IQR, range) of 8 (6-9, 4-12) segments per patient. Any EDP was identified in 71/124 (57%) of segments with EA scar. Of note, 73% of all EDPs in inferior MIs and 64% of all EDPs in anterior MI were located in 4 AHA segments, namely 3,4, 9,10 and 7,8,13,14, respectively, close to the inferior or anterior RV insertion. Such a cluster of EDP sites around the RV insertion was found in 6 (75%) patients with inferior MI and in 7 (88%) patients with anterior MI. Conclusion About 10% of EDPs are identified at sites with BV of ≥1.5mV and <3.0mV during sinus rhythm supporting the recently proposed BV threshold <3.0mV for post-MI scars. EDPs are frequently located near the RV insertion in both inferior MI and anterior MI suggesting a role of the RV insertion in the functional substrate of post-MI VT.

PO-05-150 A CASE OF QUINIDINE RESPONSIVE PURKINJE-MEDIATED POLYMORPHIC VENTRICULAR TACHYCARDIA

Polymorphic ventricular tachycardia (PMVT) has several different etiologies including ischemic ventricular fibrillation (VF), VF in coronary artery disease without active ischemia, idiopathic VF, and Torsades De Pointes (TdP). To review a case of quinidine responsive Purkinje mediated PMVT and the importance of considering alternative formulations of quinidine. N/A A 74-year-old female with no cardiac history presented with an inferior STEMI. An echocardiogram showed LV ejection fraction of 25% with multiple regional wall motion abnormalities. Left heart catheterization revealed multivessel disease for which she underwent CABG x 2 (LIMA to LAD, SVG to PDA) with intraoperative course complicated by VT requiring lidocaine drip. Ventricular arrhythmias initially seemed responsive to lidocaine; however, 4 days after CABG the patient was noted to have increased ectopic burden on telemetry and ultimately developed PMVT that required defibrillation (Fig 1A, 1B). Repeat catheterization revealed patent stents. Telemetry and ECGs were typical for Purkinje-mediated PMVT, so the patient was started on quinidine sulfate IR 400 mg every 8 hours with successful lidocaine wean and improvement in ectopic burden, with cessation of PMVT. Unfortunately, approximately 9 days after quinidine sulfate initiation the patient was noted to have rising LFTs with a normal abdominal ultrasound, platelet count, and white blood cell count, prompting discontinuation of quinidine. Without quinidine she had recurrence of PVCs that triggered bouts of PMVT (Fig 1C). PVC ablation was considered, targeting short-coupled PVCs in the border zone of scar that could be triggers for the patient’s PMVT. However, it was felt that the patient was too tenuous for ablation. Ultimately, she was trialed on quinidine gluconate ER formulation. This was started as once daily dosing and titrated up to 12-hour dosing with suppression of PVCs/PMVT and no further LFT derangements. The patient ultimately underwent ICD implant for secondary prevention and was discharged home. Purkinje mediated PMVT can occur in patients with coronary artery disease without acute ischemia. We describe a case of quinidine mediated hepatitis that was overcome by switching formulation from quinidine sulfate IR to quinidine gluconate ER. It is essential that hospitals, particularly arrhythmia referral centers, keep quinidine supplies in stock because this medication can be lifesaving during arrhythmic storms.

CE-452773-3 ASSESSMENT OF OPTIMAL VOLTAGE THRESHOLDS FOR VENTRICULAR SCAR SUBSTRATE CHARACTERIZATION

Despite the advancement in technology, historic cut-offs of <0.5mV for dense scar and 0.5-1.5mV for scar borderzone continue to be used in contemporary electrophysiology. Modern multipolar mapping catheters employ smaller electrodes and interelectrode spacing that theoretically allows for mapping with increased resolution and reduced far-field electrogram (EGM) component. We aimed to assess the optimal voltage cut-offs for ventricular scar substrate characterization using HD Grid multipolar mapping catheter against cardiac MRI-derived scar. We compared optimal voltage cut-offs using conventional bipolar sampling,Best Duplicate Algorithm and HD wave solution plus best duplicate algorithm on. A multicenter study of 33 patients with ischaemic heart disease undergoing VT ablation. Substrate mapping was performed using the high-density HD-grid multipolar mapping catheter. Bipolar voltage maps were co-registered with cardiac MRI/CT obtained before the procedure to assess the voltage characteristics of the scar defined by the image. Pre-procedure contrast-enhanced MRI data were analysed using ADAS software (Galgo medical). Data points were collected in regions of scar during (1) HD wave mapping with best duplicate algorithm on(Waveon), (2) Mapping with HD wave off and best duplicate on (Waveoff) and (3) with conventional bipolar mapping (Alloff). 29,633 voltage points were analyzed and compared to their location with the fused MRI voltage map. The median bipolar voltage for regions of dense MRI/CT scar using (Waveon) HD wave solution and best duplicate algorithm was 0.24mV (IQR 0.12 – 0.43). The median voltage with (Waveoff) HD wave off was 0.29mV (0.15 – 0.45). The median voltage with (Alloff) HD wave off and best duplicate off was 0.32mV (0.19 – 0.5). ROC analysis using AUC suggested the optimal cut-off for endocardial dense scar using (Waveon) HD wave mapping and best duplicate algorithm was 0.31mV (sensitivity: 69.6%, specificity: 60.74%) (Figure), (Waveoff) cut-off with the best duplicate and without the HD wave mapping was 0.34mV (sensitivity: 88.0%, specificity: 42.96%) and (Alloff) without wave mapping or best duplication was 0.36mV (sensitivity: 84%, specificity: 52%). Ventricular substrate characterization with newer mapping technology using narrow electrode spacing and smaller electrode sizes suggests that traditional voltage cut-offs may need revision. The optimal cut-off for dense scar delineation with the HD Grid and wave technology is 0.31mV.

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.

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.

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.

Assessment of optimal thresholds for ventricular scar substrate characterization using the high density grid multipolar mapping catheter

Abstract Funding Acknowledgements Type of funding sources: None. Background Voltage thresholds for ventricular scar definition are based on historic data collected using catheters with widely spaced bipoles in the absence of contact force. Modern multipolar mapping catheters employ smaller electrodes and interelectrode spacing that theoretically allows for mapping with increased resolution and reduced far-field electrogram (EGM) component. Despite the advancement in technology, historic cut-offs of &amp;lt;0.5mV for dense scar and 0.5-1.5mV for scar borderzone continue to be used in contemporary electrophysiology. Purpose We aimed to assess the optimal voltage cut-offs for ventricular scar substrate characterization using the HD Grid multipolar mapping catheter. Voltage cut-offs were assessed against cardiac MRI derived scar. We compared optimal voltage cut-offs using conventional bipolar sampling, the Best Duplicate Algorithm and with the HD wave solution plus best duplicate algorithm on. Methods A multicentre study of twenty patients undergoing VT ablation was conducted. Substrate mapping was performed using the high-density HD-grid multipolar mapping catheter. Bipolar voltage maps were co-registered with cardiac MRI obtained prior to the procedure to assess the voltage characteristics of scar defined by cardiac MRI (CMR) (Figure 1). Pre-procedure contrast enhanced CMR data were analysed using ADAS software (Galgo medical). Data points were collected in regions of scar during (1) HD wave mapping with best duplicate algorithm on(Waveon), (2) Mapping with HD wave off and best duplicate on (Waveoff) and (3) with conventional bipolar mapping (Alloff). Results The median bipolar voltage for regions of dense CMR scar using (Waveon) HD wave solution and best duplicate algorithm was 0.27mV (IQR 0.14 – 0.46). The median voltage with (Waveoff) HD wave off was 0.29mV (0.15 – 0.45). The median voltage with (Alloff) HD wave off and best duplicate off was 0.32mV (0.19 – 0.5). ROC analysis using AUC suggested the optimal cut-off for endocardial dense scar using (Waveon) HD wave mapping and best duplicate algorithm was 0.30mV (sensitivity: 69.6%, specificity: 60.74%), (Waveoff) cut-off with the best duplicate and without the HD wave mapping was 0.34mV (sensitivity: 69.78%, specificity: 64.46%) and (Alloff) without wave mapping or best duplication was 0.36mV (sensitivity: 84%, specificity: 52%) Figure 2. Conclusion Ventricular substrate characterization with newer mapping technology using narrow electrode spacing and smaller electrode size suggests that traditional voltage cut-offs may need revision for delineation of scar characteristics. Additionally, the ability to repeat sample in a region to obtain the best signal (Best Duplicate), and the ability to obviate the effect of wavefront direction using the HD wave solution omnipolar technology, may further increase the fidelity of scar characterization. This has important implications for mapping VT and characterizing channels in order to identify VT circuits.

Integration of structural and functional data in VT ablation -- SENSE2 protocol mapping

Abstract Funding Acknowledgements Type of funding sources: None. Background We have previously developed the sense protocol functional substrate mapping technique for VT ablation(1). However, functional substrate characterizaiton can involve protracted mapping time. Purpose We incorporated the integration of MRI data using ADAS-3D software into the mapping workflow, to integrate structural mapping information into the functional mapping substrate characterization, in order to improve procedural efficiency. Methods CMRs were performed in 20 patients with ischemic related VT and VT therapy in the previous 6 months. These were processed with the ADAS-3D software to characterize the extent of ventricular scars and also ADAS corridors which may correlate with VT channels. Focused substrate maps were then performed in patients, guided by the extent of ADAS scar and corridors, looking at the scar substrate in intrinsic rhythm and then functional channels using single extra pacing from the RV at 20ms above ERP (SENSE2 Protocol). Specifically healthy areas 2cm beyond the scar borderzone based on ADAS were not mapped, in order to reduce substrate mapping time and complete geometries were not created. Following delineation of functional channels pacemapping and entrainment mapping were used to confirm targets for ablation. The ADAS 3D MRI was integrated into the into the VT substrate map on Ensite-Precision with alignment to the aorta, RV and PA (Figure 1). We compared our data with previous functional mapping data without the integration of MRI. Results 20 patients (age 70 years; 19 male subjects) underwent ablation. Mean EF 28%. Median procedure time was 161 minutes compared with 246 minutes (in our previous study)(p=&amp;lt;0.001) Mean substrate mapping time was 32 mins vs 63 mins (p=&amp;lt;0.001). Mean ablation time was 22 mins vs 32 mins (p=0.11). 85% (17 of 20) patients were free from symptomatic VT/ anti-tachycardia pacing or implantable cardioverter defibrillator shocks at a median follow-up of 171 days. The mean VT burden was reduced from 22 events per patient in the 6 months’ pre-ablation to 1 event per patient in the median follow up period of 171 days post ablation (p=0.02). Mean shocks per-patient burden decreased from 3.5 to 0.08 in the same time period(p=0.03). Conclusion The SENSE2 protocol involves the integration of structural and functional data into the VT workflow for substrate characterization. It enables focused substrate maps to be performed without the need for complete geometry to be created in large ventricles. Outcomes compare favourably with our previous data but with significantly shorter procedure times. This streamlined workflow has the potential to improve care in VT ablation by shortening procedure times with similar outcomes which may reduce risks for the patient. Figure 1: Comparison of Voltage Map with MRI scar &amp; corridors using ADAS

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.

A novel algorithm for 3-D visualization of electrogram duration for substrate-mapping in patients with ischemic heart disease and ventricular tachycardia.

BackgroundMyocardial slow conduction is a cornerstone of ventricular tachycardia (VT). Prolonged electrogram (EGM) duration is a useful surrogate parameter and manual annotation of EGM characteristics are widely used during catheter-based ablation of the arrhythmogenic substrate. However, this remains time-consuming and prone to inter-operator variability. We aimed to develop an algorithm for 3-D visualization of EGM duration relative to the 17-segment American Heart Association model.MethodsTo calculate and visualize EGM duration, in sinus rhythm acquired high-density maps of patients with ischemic cardiomyopathy undergoing substrate-based VT ablation using a 64-mini polar basket-catheter with low noise of 0.01 mV were analyzed. Using a custom developed algorithm based on standard deviation and threshold, the relationship between EGM duration, endocardial voltage and ablation areas was studied by creating 17-segment 3-D models and 2-D polar plots.Results140,508 EGMs from 272 segments (n = 16 patients, 94% male, age: 66±2.4, ejection fraction: 31±2%) were studied and 3-D visualization of EGM duration was performed. Analysis of signal processing parameters revealed that a 40 ms sliding SD-window, 15% SD-threshold and >70 ms EGM duration cutoff was chosen based on diagnostic odds ratio of 12.77 to visualize rapidly prolonged EGM durations. EGMs > 70 ms matched to 99% of areas within dense scar (<0.2 mV), in 95% of zones within scar border zone (0.2–1.0 mV) and detected ablated areas having resulted in non-inducibility at the end of the procedure. Ablation targets were identified with a sensitivity of 65.6% and a specificity of 94.6% avoiding false positive labeling of prolonged EGMs in segments with healthy myocardium.ConclusionThe novel algorithm allows rapid visualization of prolonged EGM durations. This may facilitate more objective characterization of arrhythmogenic substrate in patients with ischemic cardiomyopathy.

Feasibility study shows concordance between image-based virtual-heart ablation targets and predicted ECG-based arrhythmia exit-sites.

We recently developed two noninvasive methodologies to help guide VT ablation: population-derived automated VT exit localization (PAVEL) and virtual-heart arrhythmia ablation targeting (VAAT). We hypothesized that while very different in their nature, limitations, and type of ablation targets (substrate-based vs. clinical VT), the image-based VAAT and the ECG-based PAVEL technologies would be spatially concordant in their predictions. The objective is to test this hypothesis in ischemic cardiomyopathy patients in a retrospective feasibility study. Four post-infarct patients who underwent LV VT ablation and had pre-procedural LGE-CMRs were enrolled. Virtual hearts with patient-specific scar and border zone identified potential VTs and ablation targets. Patient-specific PAVEL based on a population-derived statistical method localized VT exit sites onto a patient-specific 238-triangle LV endocardial surface. Ten induced VTs were analyzed and 9-exit sites were localized by PAVEL onto the patient-specific LV endocardial surface. All nine predicted VT exit sites were in the scar border zone defined by voltage mapping and spatially correlated with successful clinical lesions. There were 2.3 ± 1.9 VTs per patient in the models. All five VAAT lesions fell within regions ablated clinically. VAAT targets correlated well with 6 PAVEL-predicted VT exit sites. The distance between the center of the predicted VT-exit-site triangle and nearest corresponding VAAT ablation lesion was 10.7 ± 7.3mm. VAAT targets are concordant with the patient-specific PAVEL-predicted VT exit sites. These findings support investigation into combining these two complementary technologies as a noninvasive, clinical tool for targeting clinically induced VTs and regions likely to harbor potential VTs.

Abstract 14985: Presence of Repolarization Gradients Reverses Post-infarct Ventricular Tachycardia Exit and Entrance Sites in Personalized Digital Hearts

Introduction: Post-infarct ventricular tachycardias (VT) arise due to structural remodeling (scarring). Physiological repolarization gradients (apicobasal and transmural) exist in the human heart, but the effects on post-infarct VT dynamics are unknown. Hypothesis: We hypothesized that incorporation of repolarization gradients in personalized digital hearts of post-infarct patients impacts VT exit sites without altering the location of the VTs. Methods: 3D late-gadolinium enhanced CMR images were acquired from 7 post-infarct patients. Personalized image-based computational heart models (digital hearts) representing scar and infarct border zone distributions were constructed. Apicobasal (AB) and transmural (TM) repolarization gradients were incorporated using a validated method (Fig A). VTs were induced at baseline (no repolarization gradient) via rapid pacing in the right ventricular apex, using two pacing cycle lengths, mimicking non-invasive programmed stimulation. Pacing protocols that induced baseline VTs were repeated under AB and TM conditions. Results: Ten VTs were induced in baseline digital hearts. 8 AB VTs and 8 TM VTs were induced; the remaining 2 VTs for both AB and TM digital hearts could not be induced. 5/8 induced AB VTs had VT exit sites matching baseline VT exit sites; the remaining 3/8 AB VTs had reversed VT exit and entrance sites from the corresponding baseline VTs (Fig B, VT 1 &amp; 2). 4/8 induced TM VTs had exit sites that matched those at baseline; the remaining TM VTs had exit and entrance sites reversed from those of baseline VTs (Fig B, VT 1, 2 &amp; 3). All 8 AB VTs and 8 TM VTs had the same location as corresponding baseline VTs. Conclusion: AB and TM repolarization gradients can act to reverse VT entrance and exit sites without changing VT location. Thus, incorporation of physiological repolarization gradients into personalized digital hearts may not impact VT ablation targeting but may affect accurate prediction of VT exit or entrance sites.

Abstract 15876: Tie1 is Essential for Cardiac Repair and Myocardial Regeneration

Introduction: Cardiac lymphatics are essential in resolving interstitial fluid and inflammatory infiltrate after a myocardial infarction in adults. Little is known about the role of the lymphatic system during neonatal cardiac regeneration following injury in the perinatal animal with an immature lymphatic system. Hypothesis: Our hypothesis is that TIE1, an endothelial specific receptor tyrosine kinase essential for lymphatic development in mice, is required for myocardial repair following infarction (MI) in both neonatal and adult mice. Methods: Using an inducible and lymphatic specific deletion model, Prox1Cre-ER T2 ;Tie1 fl/fl , both mutant and non-mutant control mice undergo myocardial MI with left anterior descending coronary ligation. Adult surgery is performed at 6-8 weeks of age. Conditional Tie1 deletion is induced by ingestion of tamoxifen enriched chow 48 hours prior to adult ligation and continued until dissection is performed; cardiac function is assessed throughout this time by echocardiogram. Neonatal surgery is performed at postnatal day 2 (P2) and conditional Tie1 deletion induced with intraperitoneal tamoxifen with functional assessment by echocardiogram at P4 and P21. Results: Adult control animals had a robust lymphangiogenic response within the scar infarct border zone at 6 weeks post-MI that was not seen in mutants at 6 weeks. Furthermore, Tie1 deletion following led to a an increase in maximal injury, severe depression of cardiac function, and a blunted myocardial repair response, noted by histological analysis of the scar area. Similarly, Tie1deletion in the neonatal period resulted in markedly attenuated regenerative response with persistent scar function at P21. Conclusions: Lymphatic expression of Tie1 in the adult is required for myocardial repair following injury. In addition, lymphatic expression of Tie1 is required for optimal myocardial regeneration in the neonate even though the cardiac lymphatic system is immature in the postnatal period. Further delineation of the mechanisms involved in Tie1 mediated repair and regeneration may provide novel opportunities for therapeutic intervention following cardiac injury in both neonates and adults.