Long-Term Freedom From Ventricular Arrhythmias in ARVC With Endocardial Only Ablation: Predictors of Success.

BACKGROUND: Although the epicardial predominance of substrate abnormalities has been well demonstrated in early stages of arrhythmogenic right ventricular cardiomyopathy (ARVC), endocardial (ENDO) ablation may suffice to eliminate ventricular tachycardia (VT) in some patients. OBJECTIVES: This study aimed to report the long-term outcomes of ENDO-only ablation in ARVC patients and factors that predict VT-free survival. METHODS: We included consecutive patients with Task Force Criteria diagnosis of ARVC undergoing a first ENDO-only VT ablation between 1998 and 2020. Ablation was predominantly guided by activation/entrainment mapping for mappable VTs and pace mapping/targeting abnormal electrograms for unmappable VTs. The primary endpoint was freedom from any recurrent sustained VT after the last ENDO-only ablation. RESULTS: Seventy-four ARVC patients underwent ENDO-only VT ablation. VT noninducibility was achieved in 49 (66%) patients. During median follow-up of 6.6 years (Q1-Q3: 3.4-11.2 years), 40 (54.1%) patients remained free from any VT recurrence with rare VT ≤2 episodes in additional 12.2%. Among patients with noninducibility, VT-free survival was 75.5% during long-term follow-up. In multivariable analysis, >45 y of age at diagnosis (HR: 0.41; 95% CI: 0.17-0.98) and VT noninducibility (HR: 0.36; 95% CI: 0.16-0.80) were predictors of VT-free survival. CONCLUSIONS: Long-term VT-free survival can be achieved in over half of ARVC patients following ENDO-only VT ablation, increasing to over 75% if VT noninducibility is achieved. Our results support consideration of a stepwise ENDO-only approach before proceeding to epicardial ablation if VT noninducibility can be achieved particularly in older patients.

Endocardial HDAC3 is required for myocardial trabeculation.

Failure of proper ventricular trabeculation is often associated with congenital heart disease. Support from endocardial cells, including the secretion of extracellular matrix and growth factors is critical for trabeculation. However, it is poorly understood how the secretion of extracellular matrix and growth factors is initiated and regulated by endocardial cells. We find that genetic knockout of histone deacetylase 3 in the endocardium in mice results in early embryo lethality and ventricular hypotrabeculation. Single cell RNA sequencing identifies significant downregulation of extracellular matrix components in histone deacetylase 3 knockout endocardial cells. Secretome from cultured histone deacetylase 3 knockout mouse cardiac endothelial cells lacks transforming growth factor ß3 and shows significantly reduced capacity in stimulating cultured cardiomyocyte proliferation, which is remarkably rescued by transforming growth factor ß3 supplementation. Mechanistically, we identify that histone deacetylase 3 knockout induces transforming growth factor ß3 expression through repressing microRNA-129-5p. Our findings provide insights into the pathogenesis of congenital heart disease and conceptual strategies to promote myocardial regeneration.

Rate of Change of Initial Intrinsicoid Deflection Predicts Endocardial Versus Epicardial Ventricular Tachycardia.

BACKGROUND: Assessment of origin of ventricular tachycardias (VTs) arising from epicardial vs endocardial sites are largely challenged by the available criteria and etiology of cardiomyopathy. Current electrocardiographic (ECG) criteria based on 12-lead ECG have varying sensitivity and specificity based on site of origin and etiology of cardiomyopathy. OBJECTIVES: This study sought to test the hypothesis that epicardial VT has a slower initial rate of depolarization than endocardial VT. METHODS: We developed a method that takes advantage of the fact that electrical conduction is faster through the cardiac conduction system than the myocardium, and that the conduction system is primarily an endocardial structure. The technique calculated the rate of change in the initial VT depolarization from a signal-averaged 12-lead ECG. We hypothesized that the rate of change of depolarization in endocardial VT would be faster than epicardial. We assessed by applying this technique among 26 patients with VT in nonischemic cardiomyopathy patients. RESULTS: When comparing patients with VTs ablated using epicardial and endocardial approaches, the rate of change of depolarization was found to be significantly slower in epicardial (6.3 ± 3.1 mV/s vs 11.4 ± 3.7 mV/s; P < 0.05). Statistical significance was found when averaging all 12 ECG leads and the limb leads, but not the precordial leads. Follow up analysis by calculation of a receiver-operating characteristic curve demonstrated that this analysis provides a strong prediction if a VT is epicardial in origin (AUC range 0.72-0.88). Slower rate of change of depolarization had high sensitivity and specificity for prediction of epicardial VT. CONCLUSIONS: This study demonstrates that depolarization rate analysis is a potential technique to predict if a VT is epicardial in nature.

Computer based method for identification of fibrotic scars from electrograms and local activation times on the epi- and endocardial surfaces of the ventricles.

Cardiac fibrosis stands as one of the most critical conditions leading to lethal cardiac arrhythmias. Identifying the precise location of cardiac fibrosis is crucial for planning clinical interventions in patients with various forms of ventricular and atrial arrhythmias. As fibrosis impedes and alters the path of electrical waves, detecting fibrosis in the heart can be achieved through analyzing electrical signals recorded from its surface. In current clinical practices, it has become feasible to record electrical activity from both the endocardial and epicardial surfaces of the heart. This paper presents a computational method for reconstructing 3D fibrosis using unipolar electrograms obtained from both surfaces of the ventricles. The proposed method calculates the percentage of fibrosis in various ventricular segments by analyzing the local activation times and peak-to-peak amplitudes of the electrograms. Initially, the method was tested using simulated data representing idealized fibrosis in a heart segment; subsequently, it was validated in the left ventricle with fibrosis obtained from a patient with nonischemic cardiomyopathy. The method successfully determined the location and extent of fibrosis in 204 segments of the left ventricle model with an average error of 0.0±4.3% (N = 204). Moreover, the method effectively detected fibrotic scars in the mid-myocardial region, a region known to present challenges in accurate detection using electrogram amplitude as the primary criterion.

The correlation between subendocardial viability ratio and the degree of coronary artery stenosis in patients with coronary heart disease and its predictive value for the incidence of short-term cardiovascular events.

OBJECTIVES: This study aimed to analyze the ability of subendocardial viability ratio (SEVR) to predict the degree of coronary artery stenosis and the relationship between SEVR and the incidence of short-term cardiovascular endpoint events. METHOD: The indexes of 243 patients with chest pain were collected.. Binary logistic regression analyses were performed using the dichotomous outcome of high and non-high SYNTAX scores. Receiver operating characteristic curves were employed to comparatively analyze the diagnostic efficiencies of the indices and models. A survival analysis combined with the Cox regression analysis was performed using the Kaplan-Meier method to understand the relationship between the SEVR and the incidence of cardiovascular events within 1 year in patients with coronary heart disease (CHD). RESULTS: SEVR was significantly lower ( P  < 0.05) in the high-stenosis group than control and low-stenosis groups. The diagnostic efficacy of SEVR [area under the curve (AUC) = 0.861] was better than those of age (AUC = 0.745), ABI (AUC = 0.739), and AIx@HR75 (AUC = 0.659). The cutoff SEVR was 1.105. In patients with confirmed CHD who had been discharged from the hospital for 1 year, only SEVR affected survival outcomes (hazard ratio = 0.010; 95% confidence interval: 0.001-0.418; P  = 0.016). CONCLUSION: A significant decrease in SEVR predicted severe coronary artery stenosis, with a cutoff value of 1.105 and an accuracy of 0.861. In patients with CHD, the lower the SEVR, the higher was the rate of cardiovascular events at 1 year after hospital discharge.

Contribution of VEGF-B-Induced Endocardial Endothelial Cell Lineage in Physiological Versus Pathological Cardiac Hypertrophy.

BACKGROUND: Preclinical studies have shown the therapeutic potential of VEGF-B (vascular endothelial growth factor B) in revascularization of the ischemic myocardium, but the associated cardiac hypertrophy and adverse side effects remain a concern. To understand the importance of endothelial proliferation and migration for the beneficial versus adverse effects of VEGF-B in the heart, we explored the cardiac effects of autocrine versus paracrine VEGF-B expression in transgenic and gene-transduced mice. METHODS: We used single-cell RNA sequencing to compare cardiac endothelial gene expression in VEGF-B transgenic mouse models. Lineage tracing was used to identify the origin of a VEGF-B-induced novel endothelial cell population and adeno-associated virus-mediated gene delivery to compare the effects of VEGF-B isoforms. Cardiac function was investigated using echocardiography, magnetic resonance imaging, and micro-computed tomography. RESULTS: Unlike in physiological cardiac hypertrophy driven by a cardiomyocyte-specific VEGF-B transgene (myosin heavy chain alpha-VEGF-B), autocrine VEGF-B expression in cardiac endothelium (aP2 [adipocyte protein 2]-VEGF-B) was associated with septal defects and failure to increase perfused subendocardial capillaries postnatally. Paracrine VEGF-B led to robust proliferation and myocardial migration of a novel cardiac endothelial cell lineage (VEGF-B-induced endothelial cells) of endocardial origin, whereas autocrine VEGF-B increased proliferation of VEGF-B-induced endothelial cells but failed to promote their migration and efficient contribution to myocardial capillaries. The surviving aP2-VEGF-B offspring showed an altered ratio of secreted VEGF-B isoforms and developed massive pathological cardiac hypertrophy with a distinct cardiac vessel pattern. In the normal heart, we found a small VEGF-B-induced endothelial cell population that was only minimally expanded during myocardial infarction but not during physiological cardiac hypertrophy associated with mouse pregnancy. CONCLUSIONS: Paracrine and autocrine secretions of VEGF-B induce expansion of a specific endocardium-derived endothelial cell population with distinct angiogenic markers. However, autocrine VEGF-B signaling fails to promote VEGF-B-induced endothelial cell migration and contribution to myocardial capillaries, predisposing to septal defects and inducing a mismatch between angiogenesis and myocardial growth, which results in pathological cardiac hypertrophy.

Difference between endocardial and epicardial application of pulsed fields for targeting Epicardial Ganglia: An in-silico modelling study.

BACKGROUND: Pulsed Field Ablation (PFA) has recently been proposed as a non-thermal energy to treat atrial fibrillation by selective ablation of ganglionated plexi (GP) embedded in epicardial fat. While some of PFA-technologies use an endocardial approach, others use epicardial access with promising pre-clinical results. However, as each technology uses a different and sometimes proprietary pulse application protocol, the comparation between endocardial vs. epicardial approach is almost impossible in experimental terms. For this reason, our study, based on a computational model, allows a direct comparison of electric field distribution and thermal-side effects of both approaches under equal conditions in terms of electrode design, pulse protocol and anatomical characteristics of the tissues involved. METHODS: 2D computational models with axial symmetry were built for endocardial and epicardial approaches. Atrial (1.5-2.5 mm) and fat (1-5 mm) thicknesses were varied to simulate a representative sample of what happens during PFA ablation for different applied voltage values (1000, 1500 and 2000 V) and number of pulses (30 and 50). RESULTS: The epicardial approach was superior for capturing greater volumes of fat when the applied voltage was increased: 231 mm3/kV with the epicardial approach vs. 182 mm3/kV with the endocardial approach. In relation to collateral damage to the myocardium, the epicardial approach considerably spares the myocardium, unlike what happens with the endocardial approach. Although the epicardial approach caused much more thermal damage in the fat, there is not a significant difference between the approaches in terms of size of thermal damage in the myocardium. CONCLUSIONS: Our results suggest that epicardial PFA ablation of GPs is more effective than an endocardial approach. The proximity and directionality of the electric field deposited using an epicardial approach are key to ensuring that higher electric field strengths and increased temperatures are obtained within the epicardial fat, thus contributing to selective ablation of the GPs with minimal myocardial damage.

Left Ventricular Outflow Tract Modification for Transcatheter Mitral Valve Replacement.

Left ventricular outflow tract (LVOT) obstruction is a life-threatening complication of transcatheter mitral valve replacement. In-depth analysis of pre-procedural computed tomography enables accurate prediction of this risk. Several techniques for LVOT modification, including Laceration of the Anterior Mitral leaflet to Prevent Outflow ObtructioN, preemptive alcohol septal ablation, preemptive radiofrequency ablation, and Septal Scoring Along the Midline Endocardium, have been described as effective strategies to mitigate this risk. This review aims to explore the indications, procedural steps, and outcomes associated with these LVOT modification techniques.

Endocardial repolarization dispersion in BrS: A novel automatic algorithm for mapping activation recovery interval.

INTRODUCTION: Repolarization dispersion in the right ventricular outflow tract (RVOT) contributes to the type-1 electrocardiographic (ECG) phenotype of Brugada syndrome (BrS), while data on the significance and feasibility of mapping repolarization dispersion in BrS patients are scarce. Moreover, the role of endocardial repolarization dispersion in BrS is poorly investigated. We aimed to assess endocardial repolarization patterns through an automated calculation of activation recovery interval (ARI) estimated on unipolar electrograms (UEGs) in spontaneous type-1 BrS patients and controls; we also investigated the relation between ARI and right ventricle activation time (RVAT), and T-wave peak-to-end interval (Tpe) in BrS patients. METHODS: Patients underwent endocardial high-density electroanatomical mapping (HDEAM); BrS showing an overt type-1 ECG were defined as OType1, while those without (latent type-1 ECG and LType1) received ajmaline infusion. BrS patients only underwent programmed ventricular stimulation (PVS). Data were elaborated to obtain ARI corrected with the Bazett formula (ARIc), while RVAT was derived from activation maps. RESULTS: 39 BrS subjects (24 OType1 and 15 LTtype1) and 4 controls were enrolled. OType1 and post-ajmaline LType1 showed longer mean ARIc than controls (306 ± 27.3 ms and 333.3 ± 16.3 ms vs. 281.7 ± 10.3 ms, p = .05 and p < .001, respectively). Ajmaline induced a significant prolongation of ARIc compared to pre-ajmaline LTtype1 (333.3 ± 16.3 vs. 303.4 ± 20.7 ms, p < .001) and OType1 (306 ± 27.3 ms, p < .001). In patients with type-1 ECG (OTtype1 and post-ajmaline LType1) ARIc correlated with RVAT (r = .34, p = .04) and Tpec (r = .60, p < .001), especially in OType1 subjects (r = .55, p = .008 and r = .65 p < .001, respectively). CONCLUSION: ARIc mapping demonstrates increased endocardial repolarization dispersion in RVOT in BrS. Endocardial ARIc positively correlates with RVAT and Tpec, especially in OType1.

Endocardial Fibroelastosis Resection: When it Works and When it Does Not.

Endocardial fibroelastosis (EFE) is a thickening of the endocardial layer by accumulation of collagen and elastic fibers. Endothelial to mesenchymal transformation is proposed to be the underlying mechanism of formation. Although EFE can occur in both right and left ventricles, this article will focus on management of left ventricular EFE. Through its fibrous, nonelastic manifestation EFE restricts the myocardium leading to diastolic and systolic ventricular dysfunction and prevents ventricular growth in neonates and infants. The presence of EFE may be a marker for underlying myocardial fibrosis as well. The extent of EFE within the left ventricular cavity can be variable ranging from patchy to confluent distribution. Similarly the depth of penetration and degree of infiltration into myocardium can be variable. The management of EFE is controversial, although resection of EFE has been reported as part of the staged ventricular recruitment therapy. Following resection, EFE recurs and infiltrates the myocardium after primary resection. Herein we review the current experience with EFE resection.

Cardiac lymphoma as a cause of dyspnea in an immunosuppressed patient: the importance of the endomyocardial biopsy.

A 69-year-old man who underwent a liver transplant in 2014 due to hepatitis C virus hepatopathy was evaluated for dyspnea on exertion and chest pain.

Endocardium gives rise to blood cells in zebrafish embryos.

Previous studies have suggested that the endocardium contributes to hematopoiesis in murine embryos, although definitive evidence to demonstrate the hematopoietic potential of the endocardium is still missing. Here, we use a zebrafish embryonic model to test the emergence of hematopoietic progenitors from the endocardium. By using a combination of expression analysis, time-lapse imaging, and lineage-tracing approaches, we demonstrate that myeloid cells emerge from the endocardium in zebrafish embryos. Inhibition of Etv2/Etsrp or Scl/Tal1, two known master regulators of hematopoiesis and vasculogenesis, does not affect the emergence of endocardial-derived myeloid cells, while inhibition of Hedgehog signaling results in their reduction. Single-cell RNA sequencing analysis followed by experimental validation suggests that the endocardium is the major source of neutrophilic granulocytes. These findings will promote our understanding of alternative mechanisms involved in hematopoiesis, which are likely to be conserved between zebrafish and mammalian embryos.

Endocardial fibroelastosis causing sudden death in an infant: Autopsy case report of an unusual lesion.

ABSTRACT: Endocardial fibroelastosis is characterized by proliferation of both elastic and collagenous fibers within the endocardium, causing diffuse or localized thickening. A four-and-a-half-month-old baby was admitted to a local hospital, with a history of seizures for one day. Baby developed features of heart failure and died within one week after admission. At the post-mortem examination, heart was found to be enlarged with dilated ventricles. The endocardium of left ventricle was markedly thickened with a whitish appearance. Histopathology showed a thick layer of collagenous fibrous tissue in the endocardium, which was confirmed by Masson trichrome stain. The cause of death was offered as dilated cardiomyopathy due to endocardial fibroelastosis. The underlying mechanisms of myocardial fibrosis remain unclear. It is hypothesized that genetic, infectious, inflammatory, and nutritional processes are involved in this condition. This case highlights the importance of gross specimen examination and special staining methods to support histopathology after postmortem examination, for ascertaining the cause of death.

Bipolar endo-epicardial RF ablation: Animal feasibility study.

BACKGROUND: Bipolar radiofrequency ablation (B-RFA) is a method used to treat the arrhythmia substrate resistant to unipolar ablation. Few studies have addressed endo-epicardial B-RFA. OBJECTIVE: The aim of the study was to evaluate chronic lesions resulting from endo-epicardial B-RFA and to determine optimal settings for such procedures in an animal model. METHODS: In 7 pigs, up to 5 radiofrequency applications per animal were performed with 2 electrodes placed on both sides of the left ventricular free wall. Current was delivered for 60 seconds by a generator dedicated for B-RFA with power settings of 25, 30, 35, 40, and 50 W. RESULTS: At 12 weeks after ablation, 31 lesions were assessed. Their maximal cross-sectional area ranged from 7.2 to 68 mm2 and correlated with total power delivered (r = 0.53), with temperature increment at the endocardial catheter (r = 0.65), and inversely with temperature decrement at the epicardial catheter (r = 0.54). For power values between 30 and 40 W, the lesion area did not differ significantly (P = .92). Lesion depth ranged from 1.9 to 11 mm and correlated with impedance decrement (r = 0.5). Lesions were transmural in 8 cases. Lesion depth/wall thickness ratio was on average 0.6 ± 0.3, with the smallest value for 25 W (0.5 ± 0.3) and the largest for 50 W (0.8 ± 0.3). Steam pops occurred at a power range of 30-50 W, with an incidence of 1 in 5 applications, with 1 case of fatal tamponade at 40 W. Impedance decrement, endocardial catheter temperature increment, and endocardial electrogram amplitude decrement were greater during applications with steam pops. CONCLUSION: Chronic lesions resulting from endo-epicardial B-RFA appear smaller and less often transmural compared with acute lesions described in the literature. The incidence of steam pops during endo-epicardial B-RFA is relatively high even at low powers.

Spatiotemporal modulation of nitric oxide and Notch signaling by hemodynamic-responsive Trpv4 is essential for ventricle regeneration.

Zebrafish have a remarkable ability to regenerate injured hearts. Altered hemodynamic forces after larval ventricle ablation activate the endocardial Klf2a-Notch signaling cascade to direct zebrafish cardiac regeneration. However, how the heart perceives blood flow changes and initiates signaling pathways promoting regeneration is not fully understood. The present study demonstrated that the mechanosensitive channel Trpv4 sensed the altered hemodynamic forces in injured hearts and its expression was regulated by blood flow. In addition to mediating the endocardial Klf2a-Notch signal cascade around the atrioventricular canal (AVC), we discovered that Trpv4 regulated nitric oxide (NO) signaling in the bulbus arteriosus (BA). Further experiments indicated that Notch signaling primarily acted at the early stage of regeneration, and the major role of NO signaling was at the late stage and through TGF-ß pathway. Overall, our findings revealed that mechanosensitive channels perceived the changes in hemodynamics after ventricle injury, and provide novel insights into the temporal and spatial coordination of multiple signaling pathways regulating heart regeneration.