Border Zone Research Articles

Acetylcytidine modification of Amotl1 by N-acetyltransferase 10 contributes to cardiac fibrotic expansion in mice after myocardial infarction.

Cardiac fibrosis is a pathological scarring process that impairs cardiac function. N-acetyltransferase 10 (Nat10) is recently identified as the key enzyme for the N4-acetylcytidine (ac4C) modification of mRNAs. In this study, we investigated the role of Nat10 in cardiac fibrosis following myocardial infarction (MI) and the related mechanisms. MI was induced in mice by ligation of the left anterior descending coronary artery; cardiac function was assessed with echocardiography. We showed that both the mRNA and protein expression levels of Nat10 were significantly increased in the infarct zone and border zone 4 weeks post-MI, and the expression of Nat10 in cardiac fibroblasts was significantly higher compared with that in cardiomyocytes after MI. Fibroblast-specific overexpression of Nat10 promoted collagen deposition and induced cardiac systolic dysfunction post-MI in mice. Conversely, fibroblast-specific knockout of Nat10 markedly relieved cardiac function impairment and extracellular matrix remodeling following MI. We then conducted ac4C-RNA binding protein immunoprecipitation-sequencing (RIP-seq) in cardiac fibroblasts transfected with Nat10 siRNA, and revealed that angiomotin-like 1 (Amotl1), an upstream regulator of the Hippo signaling pathway, was the target gene of Nat10. We demonstrated that Nat10-mediated ac4C modification of Amotl1 increased its mRNA stability and translation in neonatal cardiac fibroblasts, thereby increasing the interaction of Amotl1 with yes-associated protein 1 (Yap) and facilitating Yap translocation into the nucleus. Intriguingly, silencing of Amotl1 or Yap, as well as treatment with verteporfin, a selective and potent Yap inhibitor, attenuated the Nat10 overexpression-induced proliferation of cardiac fibroblasts and prevented their differentiation into myofibroblasts in vitro. In conclusion, this study highlights Nat10 as a crucial regulator of myocardial fibrosis following MI injury through ac4C modification of upstream activators within the Hippo/Yap signaling pathway.

Pharmacological inhibition of RUNX1 reduces infarct size after acute myocardial infarction in rats and underlying mechanism revealed by proteomics implicates repressed cathepsin levels

Myocardial infarction (MI) results in prolonged ischemia and the subsequent cell death leads to heart failure which is linked to increased deaths or hospitalizations. New therapeutic targets are urgently needed to prevent cell death and reduce infarct size among patients with MI. Runt-related transcription factor-1 (RUNX1) is a master-regulator transcription factor intensively studied in the hematopoietic field. Recent evidence showed that RUNX1 has a critical role in cardiomyocytes post-MI. The increased RUNX1 expression in the border zone of the infarct heart contributes to decreased cardiac contractile function and can be therapeutically targeted to protect against adverse cardiac remodelling. This study sought to investigate whether pharmacological inhibition of RUNX1 function has an impact on infarct size following MI. In this work we demonstrate that inhibiting RUNX1 with a small molecule inhibitor (Ro5-3335) reduces infarct size in an in vivo rat model of acute MI. Proteomics study using data-independent acquisition method identified increased cathepsin levels in the border zone myocardium following MI, whereas heart samples treated by RUNX1 inhibitor present decreased cathepsin levels. Cathepsins are lysosomal proteases which have been shown to orchestrate multiple cell death pathways. Our data illustrate that inhibition of RUNX1 leads to reduced infarct size which is associated with the suppression of cathepsin expression. This study demonstrates that pharmacologically antagonizing RUNX1 reduces infarct size in a rat model of acute MI and unveils a link between RUNX1 and cathepsin-mediated cell death, suggesting that RUNX1 is a novel therapeutic target that could be exploited clinically to limit infarct size after an acute MI.

Wavefront curvature analysis derived from preprocedural imaging can identify the critical isthmus in patients with postinfarcted ventricular tachycardia

BackgroundWhere activation wavefront curvature is convexly shaped, functional conduction block can occur. ObjectiveThe purpose of this study was to determine whether left ventricular (LV) wall thickness determined from contrast-enhanced computed tomography (CT) is useful in localizing such areas in clinical postinfarction reentrant ventricular tachycardia (VT). MethodsWe evaluated data from 6 patients who underwent catheter ablation for postinfarction VT. CT imaging with inHEART processing was conducted 1–3 days before electrophysiological (EP) study to determine LV wall thickness (T). Activation wavefront curvature was approximated as ΔT/T, where ΔT represents wall thickness change. During EP study, bipolar LV VT electrograms were acquired using a high-density mapping catheter, and activation times were determined. Maps of T, ΔT/T, and VT activation were subsequently compared using statistical analyses. ResultsTwo of 6 cases exhibited dual circuit morphologies, resulting in a total of 8 VT morphologies analyzed. The LV wall near the VT isthmus location tended to be thin, on the order of a few hundred micrometers. Regions of largest ΔT/T partially coincided with the lateral isthmus boundaries where electrical conduction block occurred during VT. ΔT/T at the boundaries, measured from imaging, was significantly larger compared to values at the isthmus midline and to the global LV mean value (P <.001). ConclusionWavefront curvature measured by ΔT/T and caused by source–sink mismatch is dependent on ventricular wall thickness. Areas of high wavefront curvature partly coincide with and may be helpful in locating the VT isthmus in infarct border zones using preprocedural imaging analysis.

Increased perivascular fibrosis and pro-fibrotic cellular transition in intramyocardial blood vessels in patients with myocardial infarction

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): China Scholarship Council Background Myocardial infarction (MI) is pathologically characterized by irreversible myocardial necrosis caused by ischemia. Intramyocardial vascular dysfunction is believed to increase the risk of MI. In this study, we investigated intramyocardial blood vessels in deceased patients during the early and chronic phases of MI to explore the involvement of perivascular fibrosis and pro-fibrotic cellular transitions in the pathological process of MI. Methods Left ventricular tissue (LV) was obtained from the infarction area of autopsied patients with early-phase MI (3-6 hours old; n=23), chronic-phase MI (5-14 days old; n=12), and from non-infarcted controls (n=14). We quantified perivascular fibrosis using EVG staining and fibroblast activation protein (FAP) expression using immunohistochemistry. Co-localization of smooth muscle actin (SMA) or CD31 with fibroblast marker S100A4 indicative of transition of smooth muscle cells (SMC) and endothelial cells (EC) toward fibroblast-like cells in intramyocardial vessels was quantified using immunofluorescent microscopy. Results Compared to controls (61.03%), perivascular fibrosis was significantly elevated in MI patients (early-phase 77.20%; chronic-phase 82.58%)(p&amp;lt;0.0001), with the highest level observed in the infarct cores of chronic-phase patients (95.18%). Compared to controls, FAP expression was 3.5-fold higher in early-phase- and 15.3-fold higher in chronic-phase MI patients (p&amp;lt;0.05), wherein FAP expression again was highest in the infarct cores. Furthermore, in both early- and chronic-phase MI, SMC- and EC fibroblast-like cellular transition was increased. The fraction of SMA+S100A4+ vessels was significantly higher in early-phase MI (31.96%) and chronic-phase MI (21.9%: border zone; 37.25%: infarct core) compared to controls (8.95%)(p&amp;lt;0.05). Similarly, the fraction of CD31+S100A4+ area was significantly increased in early-phase MI (10.14%) and chronic-phase MI (8.31%: border zone 10.15%: infarct core) compared to controls (2.67%)(p&amp;lt;0.05). Conclusion We observed increased perivascular fibrosis, fibroblast activation and fibroblast-like cellular transition toward a pro-fibrotic phenotype of vascular cells in intramyocardial blood vessels in MI patients, that may contribute to the development of MI. The further increase of FAP expression and perivascular fibrosis, particularly in the infarct core, in the chronic-phase suggest that MI itself can exacerbate fibroblast activation and perivascular fibrosis, theoretically increasing the risk of reinfarction.FAP expression and perivascular fibrosispro-fibrotic vascular cellular transitio

Murine matrix metalloproteinase 13 and human matrix metalloproteinase 1 are involved in remodelling processes after myocardial infarction

Abstract Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): German Centre for Cardiovascular Research (DZHK) Background Cardiovascular diseases such as myocardial infarction (MI) remain a leading cause of death in the world. Matrix metalloproteinases (MMPs) are not only essential for the cleavage of collagen, but are also modifying inflammatory cytokines. Thus, MMPs are playing a substantial role in the context of fibrotic as well as inflammatory processes in tissue remodelling after MI. Purpose Mmp13 is the highest expressed collagenase in the murine left ventricle (LV). After ligation of the left anterior descending artery (LAD) in mice, Mmp13 is highly upregulated in the LV. Therefore, the aim of this study was to characterize the role of MMP13 in MI. In the human LV, the highest expressed collagenase is MMP1. Single nucleotide polymorphisms (SNPs) in the promotor region of MMP1 can lead to alterations in gene expression level. Therefore, we analysed the genotype of 3 SNPs in about 2000 patients admitted to the emergency department with suspected MI to reveal associations with the development of MI and outcome after MI. Methods A MMP13-knockout (KO) mouse model was examined after induction of MI and gene expression analysis, histological staining, in-situ hybridisation and hemodynamic measurements were conducted. Mmp13 expression in different cardiac cell types was investigated at quiescent stage and under ischaemic conditions, to determine the cellular origin of Mmp13 expression. Out of the human cohort, 2 patient groups (non-MI and MI) were restricted. Hazard ratios adjusted to age and male sex were assessed, to evaluate risk for MI and risk for death after MI in dependency of the SNPs. Results After activation with ischaemic secretome of cardiomyocytes, the Mmp13 expression of macrophages (6.6-fold; p=0.0286) and fibroblasts (4.9-fold; p=0.0079) was significantly increased. Under stimulation with ischaemic secretome of fibroblasts, Mmp13 expression of macrophages (4.3-fold; p=0.0286) and leukocytes (2.3-fold; p=0.0260) was significantly elevated. Additionally, in situ hybridisation revealed Mmp13 expression in immune cells in the border zone of the infarct region. While the survival of WT mice was about 50%, only very few KO mice died after MI (p=0.0107). Moreover, KO mice showed benefits in cardiac function compared to WT littermates 28 days post-MI. In the human cohort, risk for death was significantly altered between the examined genotypes in 2 of 3 investigated SNPs, indicating a role of MMP1 in the remodelling process after MI. Conclusion High levels of Mmp13 after MI originate mainly from activated macrophages and from activated fibroblasts in the infarct border zone. MMP13-deficiency is beneficial for mice after MI, leading to an improved cardiac function 28 days post-MI compared to WT controls. Analysis of SNPs of the human functional homologue of Mmp13 – MMP1 – revealed an association of MMP1 with remodelling processes after MI.

Mitral regurgitation increases systolic strains in remote zone and worsens left ventricular dyssynchrony in a swine model of ischemic cardiomyopathy.

Ischemic mitral regurgitation (IMR) imposes volume overload on the left ventricle (LV), accelerating adverse LV remodeling. In this study, we sought to investigate the impact of volume overload due to IMR on regional myocardial contractile mechanics. Ten Yorkshire swine were induced with myocardial infarction (MI) by occluding the left circumflex coronary artery (LCx). Cardiac MRI was performed at baseline (BL) and 2.5 months (2.5M) post-MI. IMR was quantified with epicardial echocardiography 3 months post-MI. The animals were then assigned to 2 groups: no/mild MR (nmMR, n = 4) and moderate/severe MR (msMR, n = 6). MRI images were analyzed to assess infarction size, end-diastolic and end-systolic volume (EDV and ESV, respectively), ejection fraction (EF), longitudinal strain (LS), circumferential strain (CS), and systolic dyssynchrony index (SDI). The myocardial region was divided into infarction, border, and remote zones based on the LCx-supplied region. There was no difference in the infarction size. Group-wise comparison of LS and CS between BL and 2.5M demonstrated that LS and CS in the infarction zone and the border zone decreased at 2.5M in both groups. However, LS and CS in the remote zone were elevated only in the msMR group (LS: -9.81 ± 3.96 vs. -12.58 ± 5.07, p < 0.01; CS; -12.78 ± 3.81 vs. -16.09 ± 3.33, p < 0.01) at 2.5M compared to BL. The SDI of CS was significantly elevated in the msMR group (0.1255 vs. 0.0974, p = 0.015) at 2.5M compared to BL. Elevated LS and CS in the remote zone were observed in moderate/severe MR and ventricular dyssynchrony. These elevated cardiac strains, coupled with ventricular dyssynchrony, may contribute to the progression of MR, thereby accelerating heart failure.

Cardiac magnetic resonance to predict appropriate therapies in secondary prevention

Abstract Introduction Implantable cardioverter-defibrillator (ICD) therapy plays a pivotal role in the management of patient’s survivors of life-threatening ventricular arrhythmias (secondary prevention). Risk of recurrence may be related to presence of myocardial scar and its components (including core mass, border zone (BZ) mass, and BZ channels) assessed with late gadolinium enhancement cardiac magnetic resonance (LGE-CMR). Purpose Our study aims to analyze the role of imaging in predicting the risk of recurrent ventricular arrhythmias and improving the risk stratification for appropriate ICD therapy in patients receiving an ICD for secondary prevention. Methods From 2015 to 2020, a total of 111 patients with LGE-CMR before ICD implantation for secondary prevention. Scar tissue including core, BZ and BZ channels were automatically detected by specialized investigational software in patients with LGE-CMR. Patients were followed until a new event was detected. Results The mean age was 65.4 ± 11.4 years; 87% were men; 55% had ischemic cardiomyopathy. The mean left ventricular ejection fraction was 37.8 % ± 14.31%. Patients were followed for a median of 3.26 years (IQR 1.4-4.9). Within the first year of follow-up 22% of patients had received an appropriate therapy, 39% within 3 years and 53% within 6 years. Chronic kidney disease and New York Heart Association (NYHA) class were associated with the primary endpoint [HR 1.94(1.06-3.55), P-value 0.032)] and [HR 1.86 (1.19-2.91), P-value 0.006)], respectively. Regarding CMR characteristics, BZ percentage was also associated with appropriate ICD therapy in the follow up [HR 1.04(1-1.08), P-value 0.048)]. Other CMR parameter, such as BZ mass, BZ core %, BZ core mass and core mass showed a trend to predict ICD therapies during follow-up. ROC curve analysis with Youden’s index defined an optimal BZ percentage cutoff value for recurrence prediction of 9.5% [HR 0.49 (0.28-0.85)]. Conclusion In patients receiving an ICD for secondary prevention, chronic kidney disease, NYHA class and BZ percentage analyzed by LGE-CMR were predictors of recurrent ventricular arrhythmia. A cutoff of BZ of 9.5% could be used to select patients with high risk of recurrence.

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&amp;lt;47% and LV end-systolic volume index of &amp;gt;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&amp;lt;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&amp;lt;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

Significance of Coherent Mapping in unveiling slow conduction zones of ventricular tachycardia substrate in ischemic cardiomyopathy

Abstract Introduction Ventricular tachycardia (VT) presents a formidable challenge, particularly in cases with extensive myocardial scar tissue, complicating critical ablation site identification. Prolonged interventions not only extend procedural durations but also heighten the risk of complications. This study aimed to assess the efficacy of coherent mapping techniques in precisely locating regions of slow conduction within scar tissue and explored potential correlations with electrophysiological markers in scar-related VT. Methods Seventeen patients (mean age: 61.6 ± 9.2 years, mean EF: 28 ± 9%) with ischemic cardiomyopathy (ICM) and frequent implantable cardioverter-defibrillator (ICD) shocks underwent high-density (&amp;gt;2000 points) left ventricular (LV) substrate mapping (15 endo, 2 epicardial) during sinus or right ventricular (RV) pacing and ablation. Coherent mapping tool was utilized for the identification of slow conduction, demonstrated by vector thickening. Bipolar low voltage areas (LVAs) below 0.5 mV were defined as dense scar, and bipolar voltage between 0.5 and 1.5 mV was defined as the border zone (Figure, panel A). Late potentials (LPs) and local abnormal ventricular activities (LAVA) were manually identified and tagged. Isochronal late activation mapping (ILAM) was also performed to elucidate the functional properties of the substrate (Figure, Panel B). Results LPs and LAVA were identified in all cases, with a mean number of LPs being 10.0 ± 7.1. Of these, 14/17 cases had LPs located in dense scar, while 4/17 cases had LPs in the border zone. The mean area of LAVA was 9.9 ± 7.7 mm², located in dense scar in 6/17 cases and in the border zone in 15/17 cases. Average deceleration zones (DZ, &amp;gt;3 isochrones in 1 cm radius) identified by ILAM was 2 ± 1. Coherent mapping consistently identified slow conduction zones adjacent to LVA in all cases, with these coherent map-based slow conduction zones (CM-SCZ) located in dense scar in 3/17 cases and in the border zone in 14/17 cases. The distance of CM-SCZ to LPs was 12.6 ± 13.9 mm (in 4 cases, LPs were recorded on the spot), and the distance to LAVAs was 18.8 ± 13.7 mm (in 2 cases, LAVAs were recorded on the spot). CM-SCZ was colocalized with DZ in 14/17 of the patients. Ablation lesions covered CM-SCZ in 10/17 cases. Over a mean follow-up duration of 11 ± 6.5 months, 4 patients experienced VT recurrence, with 3 having no ablation lesions covering CM-SCZ, and 2 patients died due to pump failure. Conclusion This study underscores the significance of coherent mapping in refining the understanding of VT substrate in ICM. Identifying and ablating CM-SCZ during substrate-based mapping may provide a potential additional benefit for VT ablation. Nevertheless, larger studies are needed to clarify the prognostic significance and validate the clinical benefits of this approach.Figure 1

Clinical validation of a novel digital twin framework for ventricular functional substrate simulation in post-infarction patients

Abstract Background Catheter ablation is a cornerstone treatment for scar related post-infarction ventricular arrhythmias. Functional substrate driven ablation strategies guided by local activation time (LAT) mapping have been proven as efficient and effective approaches, especially when dealing with large scar areas. In-silico electrophysiological modeling is emerging as a potential tool for procedural planning and guidance. Purpose To clinically validate the feasibility, diagnostic performance, and accuracy of a novel late gadolinium enhancement cardiac magnetic resonance (LGE-CMR) based digital twin framework for simulated LAT map generation in post-infarction patients and their integration with CARTO3 EAM suite. Methods Five ischemic subjects who underwent CMR-aided scar-related ventricular tachycardia ablation at our referral center were retrospectively enrolled. Their CMR derived 3D pixel-signal-intensity (PSI) maps generated with ADAS3D were processed with novel in-house software to obtain patient-specific ventricular geometry, tissue characterization, and to generate a model of Purkinje system and myocyte fiber orientation. According to local normalized pixel intensity (NPI) values, myocardial regions were marked as healthy, scar, or border-zone. Electrophysiological properties of border-zone (BZ) were modulated according to local NPI. Continuous and 8-steps isochronal endo-epicardial LAT maps were generated and imported in CARTO3 system, aligned with electroanatomical mapping (EAM), and compared at an ASE 17-segments level, in terms of sensitivity, specificity, predictive values, and accuracy to actual high-density LAT maps obtained with a multipolar catheter. Deceleration Zones (DZ) were defined as previously described (&amp;gt;3 isochrones within 1 cm radius). Results A total of 85 ASE segments (34 epicardial) were analyzed. 24 EAM segments (28%) held DZs, 40 (47%) segments harbored bipolar scar or BZ. Thirty-seven (44%) CMR segments held scar core/BZ. Thirty (35%) digital model segments harbored DZs. Generated LAT maps were successfully imported and aligned with CARTO3 EAM suite for validation. In terms of DZ localization prediction, our LAT model showed 83% sensitivity (95% CI 63%-95%), 90% specificity (95% CI 80%-96%), 77% positive predictive value (PPV) (95% CI 56%-91%), 93% negative predictive value (NPV) (95% CI 83%-98%), 88% accuracy (95% CI 79%-94%). Conclusion Our newly developed framework for LGE-CMR derived functional substrate simulation in post-infarction patients holds high sensitivity, specificity, predictive values, and accuracy for DZ localization. Further validation, with a larger sample size, is required for evaluating potential implications in clinical practice.

Termination without global capture: electrocardiographic and anatomical characteristics using 3D-electroanatomical mapping system in reentrant ventricular tachycardia

Abstract Background Termination without global capture (TWGC) is the phenomenon which a pacing stimulus applied during ventricular tachycardia (VT) terminates the tachycardia without generating a QRS complex, and is considered as an indicator for the critical component of the circuit. The details of the electrocardiographic and anatomical characteristics of the site using a 3D-electroanatomical mapping system (3D-EAM) remain unknown. Purpose This study aimed to retrospectively analyze the cases that showed TWGC during VT mapping and ablation, and to investigate the electrocardiographic characteristics and relationship with the substrate identified by 3D-EAM. Methods Of 632 cases of VT associated with structural heart disease from July, 2019 to July, 2023 at a university hospital and a university medical center, cases with TWGC were analyzed. Results TWGC was observed in 10 patients (median age 61 years, 9 males, 5 ischemic cardiomyopathy, median LVEF 31%) at least once (12 times) in 11 locations. Local capture was observed in 6. The QRS morphology generated by continued pacing after TWGC matched the clinical VT in only 5 VTs (42%). Five showed decremental conduction of stimulus to QRS interval following the TWGC. In 11 locations, 4 corresponded to scar area (&amp;lt;0.1 mV) in the voltage map, 6 to border zone (0.1-1.5 mV), and 1 had no information on 3D-EAM. Of 12 times of TWGC, 3 were at the entrance, 1 at the central isthmus, and 1 at the exit. Acute elimination of clinical VT was successful in 7 of 10. Conclusions More than half of the sites with TWGC were located at the border zone in 3D-EAM. TWGC also occurred in the central or exit area, and local capture was observed frequently.Termination without global capture

Impact of phase-correction of late-gadolinium enhancement images on quantification of scar metrics and in-silico VT-modelling in patients with an ischemic cardiomyopathy

Abstract Background Late gadolinium enhancement (LGE) is used to perform tissue characterization and has become the cornerstone to guide treatment of ventricular tachyarrhythmia (VT). Traditionally, LGE acquisition is reconstructed in two distinct forms: non-phase corrected magnitude (MIR) and phase-corrected inversion recovery (PSIR) images. However, the influence of MIR vs. PSIR on the quantification of scar metrics and the repercussion on estimating myocardial arrhythmogenicity have not been comprehensively explored. Aim This study investigated the influence of PSIR and MIR LGE on the quantification of scar metrics in a randomly selected cohort of patients with ischemic cardiomyopathy who had undergone imaging prior to ICD implantation and had received device therapy during follow-up. In addition, this study assessed how these image variations affect functional estimation of arrhythmogenicity using computational modelling. Methods ADAS 3D LV was used to generate scar maps from 2D PSIR and MIR LGE images in 10 patients. The extent of variation in scar-characteristics was evaluated by quantifying the borderzone (BZ), scar core, and conduction corridors. Electrical simulations were performed on the patient-specific anatomical models using the Virtual Induction and Treatment of Arrhythmias (VITA) framework. VITA was used to assess the electrical vulnerability of potential reentrant channels and provided the number of inducible VTs and their corresponding round-trip-time (RTT), an equivalent of VT cycle-length. Results Scar quantification using PSIR LGE resulted in a significantly larger BZ (22.1±23.7g vs. 6.2±2.7g, p &amp;lt;.001) and scar core (43.5±21.5g vs. 10.5±4g, p =.047). Furthermore, both the absolute number (6.8±4 vs. 3.4±1.5, p = .031) and weight (13±13.1g vs. 1.4±0.8g, p =.018) of conduction corridors were also higher using PSIR. VTs were inducible in 8 PSIR-models and 7 MIR-models. Despite large differences in scar characteristics, VITA metrics were not significantly different between PSIR and MIR derived models. Although, the absolute number of inducible VTs were larger for PSIR (6.2±5.4 vs. 3.4±3.1), non-parametric testing using Wilcoxon signed-rank test did not demonstrate a significant difference (Z = -1.334, p =.139). A comparable, non-significant difference was observed for mean- (117±78 vs. 79±60, p =.257) and max-RTT (181±141 vs. 120±103, p =.294) between PSIR and MIR derived models. Conclusion PSIR resulted in significantly larger BZ, scar core area, and conduction corridors. While the absolute, VITA-derived estimation of myocardial arrhythmogenicity, including inducible VTs and RTT, were higher in the PSIR-based quantification, these differences did not reach statistical significance. These results highlight important differences between two clinically applied image reconstruction techniques for the assessment of arrhythmogenic substrate, emphasizing the need for additional investigation and refinement of scar quantification techniques.

Cardiac magnetic resonance - aided ventricular tachycardia substrate ablation

Abstract Objectives To assess feasibility and reliability of Cardiac magnetic resonance (CMR)-derived pixel signal intensity (PSI) maps obtained by Three Dimensional (3D)- Late Gadolinium Enhancement (LGE) images for detecting potential targets for VT substrate ablation procedures. Background Parametric imaging with color-coded PSI maps obtained from pre-ablation 3D LGE -CMR imaging can be used for identification and characterization of arrhythmic abnormal substrate. Recent publications have shown that PSI maps permit visualization of border zone areas inside the scar. Specifically, corridors of viable tissue within the scar connecting healthy myocardium define VT corridors that may be the electrical equivalent of the abnormal conducting channels on the electroanatomical mapping (EAM). Methods 8 patients with scar-dependent monomorphic VTs who underwent 3D-LGE CMR imaging prior to substrate ablation were included in the study. The studies were performed at 1.5T scanner. We obtained two data sets of 3D whole heart LGE imaging with high resolution. Patients underwent two acquisitions: the conventional respiratory navigated, electrocardiographically-gated 3D fast gradient echo (1.3slice thickness, 256x256 matrix acquisition) and the image-navigated isotropic high resolution 3D GE with Dixon water-fat separation. 3D LGE-CMR images were processed with ADAS-VT software to produce a 3-dimensional model of the heart with 10 layers from the endocardium to epicardium and PSI maps color-coded from the LGE data projected to each of the shells (Figure 1). In the LGE-CMR PSI maps, VT corridors were obtained automatically by the ADAS VT software. Subsequently, data were given to the electrophysiologists and merged with the CARTO3 system EAM data obtained for the ablation (Figure2). CMR information was used to facilitate the identification of target ablation sites in the areas identified by CMR as abnormal substrate and radiofrequency was applied in the presence of both a pathological electrogram (EGM) and a VT corridor as identified by CMR. Results There was a 95% agreement between the abnormal conducting channels as detected by abnormal electrograms in the EAM and the VT corridors identified by 3D LGE CMR imaging. In two occasions, there was one VT corridor that did not correlate with abnormal electrograms and was not ablated. The two 3D LGE sequences used for ADAS-VT corridors analysis showed complete agreement in the number and location of VT corridors. Mean acquisition time for 3D LGE imaging was 11±4minutes for the conventional fast gradient echo sequence, and 5±2minutes for the novel 3D self-image navigated LGE sequence. The image quality of 3D LGE was superior with the Dixon fat-water separation. Overall CMR-aided VT ablation reduced the procedural and fluoroscopy time by 40%. Conclusions CMR-aided VT ablation is feasible, reliable and significantly reduces the procedural time.

Multipolar Electrograms: A New Configuration That Increases the Measurement Accuracy of Intracardiac Signals

BackgroundAccurate measurements of intracardiac electrograms (EGMs) remain a clinical challenge because of the suboptimal attenuation of far-field potentials. Multielectrode mapping catheters provide an opportunity to construct multipolar instead of bipolar EGMs for rejecting common far-field potentials recorded from a multivectorial space. ObjectivesThe purpose of this study was to develop a multipolar EGM and compare its characteristics to those of bipolar EGMs MethodsUsing a 36-electrode array catheter (Optrell-36, Biosense Webster), a far-field component was mathematically constructed from clusters of electrodes surrounding each inspected electrode. This component was subtracted from the unipolar waveform to produce a local unipolar, referred to as a “multipolar EGM.” The performance of multipolar EGMs was evaluated in 7 swine with healed anteroseptal infarction. ResultsMultipolar EGMs proved superior in attenuating far-field potentials in infarct border zones, increasing the near-field to far-field ratio from 0.92 ± 0.2 to 2.25 ± 0.3 (P < 0.001). Removal of far-field components reduced the voltage amplitude (P < 0.001) and enlarged the infarct surface area (P = 0.02), aligning more closely with histological findings. Of 379 EGMs with ≥20 ms activation time difference between bipolar and multipolar EGMs, 95.3% (361 of 379) were accurately annotated using multipolar EGMs, while annotation based on bipolar EGM was predominantly made on far-field components. ConclusionsMultielectrode array catheters provide a unique platform for constructing multipolar EGMs. This new EGM may be beneficial for "purifying" local potentials within a complex electrical field, resulting in more accurate voltage and activation maps.

Platelets Induce Cell Apoptosis of Cardiac Cells via FasL after Acute Myocardial Infarction.

Acute myocardial infarction (AMI) is one of the leading causes of death worldwide. Cell apoptosis in the myocardium plays an important role in ischemia and reperfusion (I/R) injury, leading to cardiac damage and dysfunction. Platelets are major players in hemostasis and play a crucial role in vessel occlusion, inflammation, and cardiac remodeling after I/R. Here, we studied the impact of platelets on cell apoptosis in the myocardium using a close-chest mouse model of AMI. We found caspase-3-positive resident cardiac cells, while leukocytes were negative for caspase-3. Using two different mouse models of thrombocytopenia, we detected a significant reduction in caspase-3 positive cells in the infarct border zone after I/R injury. Further, we identified platelet FasL to induce cell apoptosis via the extrinsic pathway of Fas receptor activation of target cells. Mechanistically, hypoxia triggers platelet adhesion to FasR, suggesting that platelet-induced apoptosis is elevated after I/R. Platelet-specific FasL knock-out mice showed reduced Bax and Bcl2 expression, suggesting that platelets modulate the intrinsic and extrinsic pathways of apoptosis, leading to reduced infarct size after myocardial I/R injury. Thus, a new mechanism for how platelets contribute to tissue homeostasis after AMI was identified that should be validated in patients soon.

Biomarker Periodic Repolarization Dynamics Indicates Enhanced Risk for Arrhythmias and Sudden Cardiac Death in Myocardial Infarction in Pigs.

Periodic repolarization dynamics (PRD) is an electrocardiographic biomarker that captures repolarization instability in the low frequency spectrum and is believed to estimate the sympathetic effect on the ventricular myocardium. High PRD indicates an increased risk for postischemic sudden cardiac death (SCD). However, a direct link between PRD and proarrhythmogenic autonomic remodeling has not yet been shown. We investigated autonomic remodeling in pigs with myocardial infarction (MI)-related ischemic heart failure induced by balloon occlusion of the left anterior descending artery (n=17) compared with pigs without MI (n=11). Thirty days after MI, pigs demonstrated enhanced sympathetic innervation in the infarct area, border zone, and remote left ventricle paralleled by altered expression of autonomic marker genes/proteins. PRD was enhanced 30 days after MI compared with baseline (pre-MI versus post-MI: 1.75±0.30 deg2 versus 3.29±0.79 deg2, P<0.05) reflecting pronounced autonomic alterations on the level of the ventricular myocardium. Pigs with MI-related ventricular fibrillation and SCD had significantly higher pre-MI PRD than pigs without tachyarrhythmias, suggesting a potential role for PRD as a predictive biomarker for ischemia-related arrhythmias (no ventricular fibrillation versus ventricular fibrillation: 1.50±0.39 deg2 versus 3.18±0.53 deg2 [P<0.05]; no SCD versus SCD: 1.67±0.32 deg2 versus 3.91±0.63 deg2 [P<0.01]). We demonstrate that ischemic heart failure leads to significant proarrhythmogenic autonomic remodeling. The concomitant elevation of PRD levels in pigs with ischemic heart failure and pigs with MI-related ventricular fibrillation/SCD suggests PRD as a biomarker for autonomic remodeling and as a potential predictive biomarker for ventricular arrhythmias/survival in the context of MI.

Cosmogenic nuclide-derived downcutting rates of canyons within large limestone plateaus of southern Massif Central (France) reveal a different regional speleogenesis of karst networks

Abstract. We present 35 new burial ages (27 sites) based on 26Al / 10Be ratios of terrestrial cosmogenic radionuclides measured in clasts and sediments deep within 12 caves in the southern Massif Central, France. Our results, together with previously published burial ages, verify that cave morphogenesis has been continuously active in this region for at least the past ∼ 6 Myr. Combining sample burial ages with their associated cave elevation above the modern stream bed gives a mean regional incision rate of 88 ± 5 m Ma−1 for the Grands Causses area. South of the Cevennes Fault Zone bordering the Grands Causses, the incision rate is 43 ± 5 m Ma−1, suggesting that this difference might be accommodated by the fault zone. Sediment burial ages from caves which are not located on river valley flanks or cliff walls are surprisingly too young compared to their expected ages when calculated using this regional average river incision rate. This suggests that the classical epigenic speleogenesis model that presumes a direct correlation between cave level development and regional base level lowering does not apply for the study area. Therefore, we propose that regional speleogenesis is mainly controlled by the removal of ghost rocks by headward erosion from river canyons to central parts of the plateaus, emptying incipient primokarst passages to create cave systems. Our results suggest a continuum process from hypogene primokarst composed of passages filled with ghost rock to one of epigene karst dynamics emptying these passages and creating cave networks. We propose that these processes are the major mechanism in the southern Massif Central that initiates speleogenesis and controls the geometry of the networks. In this region, tiered karst cannot be associated with the pace of incision of the major rivers but must be explained by former ghost rock (or hypogene) processes.

Infliximab Limits Injury in Myocardial Infarction.

The purpose of this study was to investigate a therapeutic approach targeting the inflammatory response and consequent remodeling from ischemic myocardial injury. Coronary thrombus aspirates were collected from patients at the time of ST-segment-elevation myocardial infarction and subjected to array-based proteome analysis. Clinically indistinguishable at myocardial infarction (MI), patients were stratified into vulnerable and resilient on the basis of 1-year left ventricular ejection fraction and death. Network analysis from coronary aspirates revealed prioritization of tumor necrosis factor-α signaling in patients with worse clinical outcomes. Infliximab, a tumor necrosis factor-α inhibitor, was infused intravenously at reperfusion in a porcine MI model to assess whether infliximab-mediated immune modulation impacts post-MI injury. At 3 days after MI (n=7), infliximab infusion increased proregenerative M2 macrophages in the myocardial border zone as quantified by immunofluorescence (24.1%±23.3% in infliximab versus 9.29%±8.7% in sham; P<0.01). Concomitantly, immunoassays of coronary sinus samples quantified lower troponin I levels (41.72±7.34 pg/mL versus 58.11±10.75 pg/mL; P<0.05) and secreted protein analysis revealed upregulation of injury-modifying interleukin-2, -4, -10, -12, and -18 cytokines in the infliximab-treated cohort. At 4 weeks (n=12), infliximab treatment resulted in significant protective influence, improving left ventricular ejection fraction (53.9%±5.4% versus 36.2%±5.3%; P<0.001) and reducing scar size (8.31%±10.9% versus 17.41%±12.5%; P<0.05). Profiling of coronary thrombus aspirates in patients with ST-segment-elevation MI revealed highest association for tumor necrosis factor-α in injury risk. Infliximab-mediated immune modulation offers an actionable pathway to alter MI-induced inflammatory response, preserving contractility and limiting adverse structural remodeling.

Distribution of Silent Cerebral Infarcts in Adults With Sickle Cell Disease.

Previously we demonstrated that 90% of infarcts in children with sickle cell anemia occur in the border zone regions of cerebral blood flow (CBF). We tested the hypothesis that adults with sickle cell disease (SCD) have silent cerebral infarcts (SCIs) in the border zone regions, with a secondary hypothesis that older age and traditional stroke risk factors would be associated with infarct occurrence in regions outside the border zones. Adults with SCD 18-50 years of age were enrolled in a cross-sectional study at 2 centers and completed a 3T brain MRI. Participants with a history of overt stroke were excluded. Infarct masks were manually delineated on T2-fluid-attenuated inversion-recovery MRI and registered to the Montreal Neurological Institute 152 brain atlas to generate an infarct heatmap. Border zone regions between anterior, middle, and posterior cerebral arteries (ACA, MCA, and PCA) were quantified using the Digital 3D Brain MRI Arterial Territories Atlas, and logistic regression was applied to identify relationships between infarct distribution, demographics, and stroke risk factors. Of 113 participants with SCD (median age 26.1 years, interquartile range [IQR] 21.6-31.4 years, 51% male), 56 (49.6%) had SCIs. Participants had a median of 5.5 infarcts (IQR 3.2-13.8). Analysis of infarct distribution showed that 350 of 644 infarcts (54.3%) were in 4 border zones of CBF and 294 (45.6%) were in non-border zone territories. More than 90% of infarcts were in 3 regions: the non-border zone ACA and MCA territories and the ACA-MCA border zone. Logistic regression showed that older participants have an increased chance of infarcts in the MCA territory (odds ratio [OR] 1.08; 95% CI 1.03-1.13; p = 0.001) and a decreased chance of infarcts in the ACA-MCA border zone (OR 0.94; 95% CI 0.90-0.97; p < 0.001). The presence of at least 1 stroke risk factor did not predict SCI location in any model. When compared with children with SCD, in adults with SCD, older age is associated with expanded zones of tissue infarction that stretch beyond the traditional border zones of CBF, with more than 45% of infarcts in non-border zone regions.

Geotourism is one of the important pillars of tourism, which plays an important role in the economic and social development of regions, and this issue is doubly important in border regions. Considering that one of the ways to create security in the border zone is the economic development of the region, therefore, the development of geotourism in the border zone

Geotourism is one of the important pillars of tourism, which plays an important role in the economic and social development of regions, and this issue is doubly important in border regions. Considering that one of the ways to create security in the border zone is the economic development of the region, therefore, the development of geotourism in the border zone