Atrial Myocardium Research Articles

Experimental study on the effect of chlorhexidine gluconate (CG)-induced atrial fibrillation on renal water and sodium metabolism

To construct an animal model of atrial fibrillation and observe the effect of acute atrial fibrillation on renal water and sodium metabolism in mice. A total of 20 C57 mice were randomly assigned to 2 groups (n = 10/group): control group (CON) and atrial fibrillation group (AF). The mice model of atrial fibrillation was induced by chlorhexidine gluconate (CG) in combination with transesophageal atrial spacing. The urine of the two groups of mice was collected, and then we calculate the urine volume and urine sodium content. The expression of TGF-β and type III collagen in the atrial myocardium of the two groups was detected by immunohistochemistry and Western Blot. The levels of CRP and IL-6 in blood were observed by ELISA, and the NF-κB, TGF-β, collagen type III, AQP2, AQP3, AQP4, ENaC-β, ENaC-γ, SGK1 and NKCC proteins in the kidneys of the two groups of mice was observed by Western Blot. Compared with CON, the expression of TGF-β and type III collagen in the atrial myocardium of the mice in AF were increased, the levels of CRP and IL-6 in the blood in AF were increased, and the renal NF-κB, TGF-β, type III collagen AQP2, AQP3, ENaC-β, ENaC-γ, SGK1 and NKCC protein expression in AF were up-regulated. The level of urine volume and urine sodium content in AF were significantly reduced. In the acute attack of atrial fibrillation, the formation of renal inflammatory response and fibrosis is activated, and the renal water and sodium metabolism is hindered, which is related to the up-regulated of the expressions of renal NKCC, ENaC and AQPs.

Role of autophagy in simulated ischemic-reperfused left atrial myocardium

Background and aimAutophagy has recently emerged as a potential and promising therapeutic approach to maintain cardiac cellular homeostasis. The aim of the present study was to investigate the role of autophagy in the ischemic-reperfused atrial myocardium. MethodsIsolated rat left atria subjected to simulated ischemia-reperfusion were used. The bathing medium contained either 10 mM d-glucose or 10 mM d-glucose and 1.2 mM palmitate. 3-methyladenine (3-MA) was used as pharmacological autophagy inhibitor. ResultsLC3-II/LC3-I ratio, an indicator of autophagosome formation, was significantly enhanced during reperfusion, this increase being slowed by the exposure to high palmitate concentration and prevented by 3-MA. Beclin-1 was significantly increased during reperfusion period in both metabolic conditions, and pharmacological inhibition of AMPK partially prevented LC3-II/LC3-I ratio increase. Autophagy inhibition significantly increased mitochondrial damage and impaired mitochondrial ATP synthesis rate at reperfusion. Tissue ATP content recovery and contractile reserve were also reduced during this period, these effects being more pronounced either in 3-MA treated atria and ischemic-reperfused atria incubated with palmitate. Moreover, severe tachyarrhythmias were observed in the presence of 3-MA, in both metabolic conditions. This phenomenon was partially prevented by mitochondrial inner membrane ion channels blocker, PK11195. ConclusionPresent study provides new insights into the role of autophagy in ischemic-reperfused atrial myocardium. The observation of greater deterioration in mitochondrial structure and function when this process was inhibited, suggests an association between autophagy and the structural and functional preservation of mitochondria. Exogenous metabolic substrates, to which the myocardium is exposed during ischemia-reperfusion, might not affect this process.

Empagliflozin suppresses mitochondrial reactive oxygen species generation and mitigates the inducibility of atrial fibrillation in diabetic rats.

Recent studies have demonstrated that sodium-glucose co-transporter-2 inhibitors (SGLT2-i) reduce the risk of atrial fibrillation (AF) in patients with diabetes mellitus (DM), in which oxidative stress due to increased reactive oxygen species (ROS) contributes to the pathogenesis of AF. We aimed to further investigate this, and examine whether the SGLT2-i empagliflozin suppresses mitochondrial-ROS generation and mitigates fibrosis. A high-fat diet and low-dose streptozotocin treatment were used to induce type-2 DM (T2DM) in Sprague-Dawley rats. The rats were randomly divided into three groups: control, DM, and DM treated with empagliflozin (30 mg/kg/day) for 8 weeks. The mitochondrial respiratory capacity and ROS generation in the atrial myocardium were measured using a high-resolution respirometer. Oxidative stress markers and protein expression related to mitochondrial biogenesis and dynamics as well as the mitochondrial morphology were examined in the atrial tissue. Additionally, mitochondrial function was examined in H9c2 cardiomyoblasts. Atrial tachyarrhythmia (ATA) inducibility, interatrial conduction time (IACT), and fibrosis were also measured. Inducibility of ATA, fibrosis, and IACT were increased in rats with DM when compared to controls, all of which were restored by empagliflozin treatment. In addition, the rats with DM had increased mitochondrial-ROS with an impaired complex I-linked oxidative phosphorylation capacity. Importantly, empagliflozin seemed to ameliorate these impairments in mitochondrial function. Furthermore, empagliflozin reversed the decrease in phosphorylated AMPK expression and altered protein levels related to mitochondrial biogenesis and dynamics, and increased mitochondrial content. Empagliflozin also improved mitochondrial function in H9c2 cells cultured with high glucose medium. These data suggest that empagliflozin has a cardioprotective effect, at least in part, by reducing mitochondrial ROS generation through AMPK signaling pathways in the atrium of diabetic rats. This suggests that empagliflozin might suppress the development of AF in T2DM.

Atrial inflammation and microvascular thrombogenicity are increased in deceased COVID-19 patients

BackgroundHistopathological studies have shown inflammation, cardiomyocyte injury, and microvascular thrombosis in the ventricular myocardium of patients with coronavirus disease 2019 (COVID-19). However, although atrial dysfunction is common in COVID-19, little is known about histopathological changes in the atria of the heart. We therefore analyzed inflammation, cardiomyocyte injury, and microvascular thrombogenicity in the atria of deceased patients with COVID-19. MethodsAtrial tissue was obtained from autopsied COVID-19 (n=16) patients and control patients (n=10) and analyzed using immunohistochemistry. The infiltration of CD45+ leukocytes, CD3+ T lymphocytes, CD68+ macrophages, MPO+ neutrophils, and Tryptase+ mast cells were quantified as well as cardiomyocyte damage and microvascular thrombosis. In addition, Tissue Factor (TF) and Factor XII (FXII) were quantified as markers of microvascular thrombogenicity. ResultsThe numbers of lymphocytes, macrophages, and neutrophils were significantly increased in the atrial myocardium and epicardial atrial adipose tissue of COVID-19 patients compared with the control group. This was accompanied by dispersed cardiomyocyte injury, the occasional presence of microvascular thrombosis, and an increased presence of TF and FXII in the microvascular endothelium. ConclusionsSevere COVID-19 induces inflammation, cardiomyocyte injury, and microvascular thrombosis in the atria of the heart.

Pulmonary vein isolation using pulse field ablation: Acute results from a multicentric registry

Pulsed field ablation (PFA) is a nonthermal ablative modality using a strong electrical field created around a dedicated catheter to produce pores in the cellular membrane. As the amount of energy required to produce electroporation is highly tissue dependent, the atrial myocardium can be specifically targeted while sparing adjacent tissues. Theoretically, this new ablation modality could increase the safety of pulmonary vein isolation (PVI) procedures compare to PVI using thermal energies. Real-life clinical data are still lacking regarding feasibility and safety of PFA. To assess feasibility and safety of PVI performed using PFA. We included all patients who underwent PVI for symptomatic atrial fibrillation (AF) using PFA in 3 hospitals (6 operators) between June 2021 and April 2022. All procedures were performed under general anaesthesia or deep sedation. After patients received IV heparin and achieved ACT > 300 s, a 12 Fr multi-electrode pentaspline PFA catheter (Farawave, Farapulse Inc.) was advanced through a 13 Fr deflectable sheath into the left atrium. The catheter was positioned so that the splines achieved circumferential contact at the PV antra. 2 applications (2.5 sec and 2 kV per application) were performed in the “basket” configuration, then the catheter was slightly rotated (30–40°) before delivery of 2 additional applications. This sequence of ablation was repeated in the “flower” configuration. This protocol was applied at each PV. PVI was assessed with the Farawave catheter. The population consisted of 126 patients (76 paroxysmal AF, 50 persistent AF < 6 months) with a mean age of 61 ± 12 yo. Left atrial dimension was normal in 72 patients (57%) and enlarged in 54 (43%). The mean procedure duration was 47 ± 20 min, and mean fluoroscopy duration was 17 ± 7 min. The pulmonary vein signal completely disappeared after the first PFA application for each targeted vein and PVI was confirmed for all veins in all patients at the end of the procedure. Pericardial effusion occurred in 3 patients (2.4%), 2 requiring percutaneous drainage. No other complications were observed (Fig. 1). PVI performed with PFA is safe and feasible without compromising procedure and scopy durations. Further data are necessary regarding mid- and long-term efficacy.

Atrial Endocardial Unipolar Voltage Mapping for Detection of Viable Intramural Myocardium: A Proof-of-Concept Study

Endocardial bipolar voltage amplitude is largely derived from endocardial and subendocardial wall layers. This may result in situations of low bipolar voltage amplitude despite the presence of mid-myocardial including epicardial (ie, intramural-epicardial) viable myocardium. This study examined the utility of endocardial unipolar voltage mapping for detection of viable intramural-epicardial atrial myocardium. In 15 swine, an atrial intercaval ablation line with an intentional gap was created. Animals survived for 6 to 8 weeks before electroanatomical mapping followed by sacrifice. Gaps were determined by the presence of electrical conduction and classified based on the histopathologiclly layer(s) of viable myocardium into the following: (1) transmural, (2) endocardial, and (3) intramural-epicardial. Voltage data from healthy, scar, and gap points were exported into excel. The sensitivity and specificity of bipolar and unipolar voltage amplitude to detect intramural-epicardial gaps were compared using receiver operating characteristic analysis. In 9 of 15 (60%) swine, a focal ablation gap was detected in the intercaval line, while in the remainder 6 of 15 (40%), the line was complete without gaps. Gaps were classified into transmural (n=3), endocardial (n=3), or intramural-epicardial (n=3). Intramural-epicardial gaps were characterized by very low bipolar voltage amplitude that was similar to areas with transmural scar (P=0.91). In comparison, unipolar voltage amplitude in intramural-epicardial gaps was significantly higher compared to transmural scar (P<0.001). Unipolar voltage amplitude had higher sensitivity (93% versus 14%, respectively) and similar specificity (95% versus 98%, respectively) to bipolar voltage for detection of intramural-epicardial gaps. Atrial unipolar voltage mapping may be a useful technique for identifying viable intramural-epicardial myocardium in patients with endocardial scar.

Peri-Coronary Sinus Flutter: A Unique Form of an Atypical Atrial Flutter. A Case Report

The coronary sinus musculature connects to the right and the left atrium, forming electrical interatrial bridges and can be a critical part of various left atrial and biatrial flutter circuits. We herein present a rare case of a macroreentrant tachycardia around only the coronary sinus using interatrial connections at its orifice and the inferolateral left atrium and the adjacent left atrial myocardium. Crucial for the identification of this macroreentrant circuit was the record of low voltage signals of epicardial sleeves through an endocardially placed multipolar HD-mapping catheter with small flat electrodes. The peri-Coronary sinus flutter should always be included in the differential diagnosis of an atypical atrial flutter.

MORPHOLOGICAL CHARACTERISTICS OF THE ENDOCRINE FUNCTION OF THE HEART IN COMORBID PATHOLOGY.

Aim: To study the ultrastructural remodeling of atrial myoendocrine cells (AMC) of the atrial myocardium in streptozotocin-induced diabetes (SID) under chronic immobilization stress (CIS). Materials and methods: 40 sexually mature white male rats (body weight 150-180 g) were included in the study. Four groups were formed: group 1 - animals with comorbid pathology (SID and CIS), group 2 - animals with SID, group 3 - animals with CIS, group 4 - intact animals. Results: On the 14th day of the development of SID and CIS, an increase in the functional activity of AMC is noted, which is confirmed by hyperplasia and hypertrophy of the protein-synthesizing apparatus, an increase in the volume density of secretory granules (SG), especially diffusing ones, and indicates enhanced release of atrial natriuretic peptide (ANP) from cells during the experiment. On the 56th day of the experiment, in groups 1 and 2 of , destructive changes in AMC were noted, such as vacuolar and balloon dystrophy, colliquative and partial necrosis. At the same time, the functional activity of AMC of different regions of the myocardium significantly. In animals with CIS, the volume density of young and diffusing SG in AMC is decreased. Conclusions: Therefore, in the early stages of the development of SID and CIS, an increase in the morpho-functional activity of AMC is noted. The long course of SID and its combination with CIS lead to destructive changes in AMC and to decrease in their secretory activity.

Mechanisms of Modulation of Adrenergic Regulation of Spontaneous Activity Rate and Atrial Myocardial Contractility in Early Postnatal Ontogeny in Rats

We studied combined effect of the β1,2-adrenoreceptor agonist isoproterenol and the Y1,5 receptor agonist [Leu31, Pro34]neuropeptide Y on the frequency of spontaneous activity and myocardial contractility in 21- and 100-day-old rats. Isoproterenol increased the frequency of spontaneous activity and reduced the main parameters of isometric contraction of the atrial myocardium. When [Leu31, Pro34]neuropeptide Y was added, the frequency of spontaneous activity and the negative inotropic and the positive chronotropic effects of isoproterenol were reduced in 100-day-old rats. In 21-day-olds rats, a tendency to a decrease in the effect of isoproterenol was observed.

Effects of catheter ablation of atrial fibrillation on the biomarker profile.

Following catheter ablation for atrial fibrillation (AF), there are dynamic changes in the atrial myocardium associated with damage to and necrosis of atrial tissue and other procedure related changes in rhythm and anticoagulation. Early time-dependent changes in biomarkers of necrosis, inflammation, and coagulation have been reported. This study examines mid-term (4-8weeks post-ablation) changes in biomarkers and explores their ability to predict AF recurrence at one-year. Twenty-seven patients (mean age 65.4±9.7 years, 30% female) undergoing catheter ablation for AF had peripheral venous blood samples obtained at the time of ablation and 4-8weeks later. All samples were processed to obtain plasma which was frozen for subsequent analysis. Coagulation studies were performed at the Northwestern Special Hemostasis Laboratory: VWF, ADAMTS13, PAI-1, D-dimer, and TAT complexes. A commercial lab analyzed samples for CRP, cystatin C, fibrinogen, galectin, IL-6, MMP-2, myoglobin, NT-proBNP, PAI-1, TIMP-1, TIMP-2, TPA, and VWF. Significant changes were noted with higher levels of ADAMTS13 (p <0.0001), fibrinogen (p =0.004), MMP-2 (p =0.0002), TIMP-2 (p =0.003), and TPA (p =0.001) compared to lower levels of TAT (p <0.0001) and NT-proBNP (p =0.0001) at follow up post-ablation. One year after ablation, AF had recurred in 11/26 (42%) of patients. None of the biomarker changes predicted the 1-year outcome, and there was no significant association with the use of warfarin versus rivaroxaban. In patients undergoing catheter ablation for AF, there were significant changes in pre- vs post-ablation levels of multiple biomarkers. However, these changes were not associated with 1-year outcome of AF recurrence.

608 PEAK ATRIAL SYSTOLIC LONGITUDINAL STRAIN (PALS) AS AN EARLY PARAMETER OF CANCER THERAPY-RELATED CARDIAC DYSFUNCTION

Abstract Background Trastuzumab (TZ) is widely used for his key role in HER2 positive breast cancer. However, the most concerning cardiovascular complication is cardiotoxicity. Many studies have highlighted the importance of screening for subclinical myocardial dysfunction using left ventricular ejection fraction (LVEF) and global longitudinal strain (GLS). However, there are only few studies investigating a possible atrial damage. Purpose Aim of this study was to analyze the modification peak atrial systolic longitudinal strain (PALS) in patients undergoing therapy with TZ in a follow-up period of 12 months. The fluctuation of left atrial function parameters under chemotherapy was evaluated focusing the attention on those patients who developed cancer therapy–related cardiac dysfunction (CTRCD). Methods 116 women affected by breast cancer treated with TZ were enrolled. Each patient underwent a complete echocardiography at baseline and every 3 months. Exclusion criteria were poor quality imaging and lack of a complete follow up with consequent missing data. CTRCD was defined as a decrease in the left ventricular ejection fraction of &amp;gt;10 percentage points to a value &amp;lt;53% at any time of follow-up. 2D-Speckle tracking analysis was performed at baseline and at each examination using Tomtec software to analyze both atrial and left ventricular function. Trends of GLS, and PALS during 12 months-follow up periods were analyzed. Additionally, we explored if diabetes and renal impairment were associated with more prevalent atrial subclinical disfunction as demonstrated in previous studies. Results A total of 10 patients (9%) developed cancer therapy–related cardiac dysfunction. A significant reduction in GLS compared to the baseline was observed during the whole follow-up (p=0.05), starting in the first six months of treatment (-21 ± 2% vs -17 ± 2%, p= 0.021). Interestingly, PALS showed a similar trend with a significant decrease during the whole 12 months-follow up (p=0.012), starting in the first 3 months (45 ± 9% vs 35 ± 8%, p=0.001). 6 patients presented a diagnosis of diabetes at baseline, and presented lower PALS compared to the non-diabetic counterpart (38± 10% vs 49 ± 12% p=0.03). 2 patients presented a significant renal impairment (eGFR ≤30 ml/min). Similarly, these patients presented a lower PALS at baseline (32 ± 7% and 48 ± 7%; p=0.055). Conclusions In patients treated with Trastuzumab the development of left atrial impairment is frequent and PALS modifications seem to precede GLS variations in patients with CTRCD, suggesting a possible cardiotoxic effect of such therapy on both atrial and left ventricular myocardium and physiology.

Mechanisms and Management of Thyroid Disease and Atrial Fibrillation: Impact of Atrial Electrical Remodeling and Cardiac Fibrosis.

Atrial fibrillation (AF) is the most common cardiac arrhythmia associated with increased cardiovascular morbidity and mortality. The pathophysiology of AF is characterized by electrical and structural remodeling occurring in the atrial myocardium. As a source of production of various hormones such as angiotensin-2, calcitonin, and atrial natriuretic peptide, the atria are a target for endocrine regulation. Studies have shown that disorders associated with endocrine dysregulation are potential underlying causes of AF. The thyroid gland is an endocrine organ that secretes three hormones: triiodothyronine (T3), thyroxine (T4) and calcitonin. Thyroid dysregulation affects the cardiovascular system. Although there is a well-established relationship between thyroid disease (especially hyperthyroidism) and AF, the underlying biochemical mechanisms leading to atrial fibrosis and atrial arrhythmias are poorly understood in thyrotoxicosis. Various animal models and cellular studies demonstrated that thyroid hormones are involved in promoting AF substrate. This review explores the recent clinical and experimental evidence of the association between thyroid disease and AF. We highlight the current knowledge on the potential mechanisms underlying the pathophysiological impact of thyroid hormones T3 and T4 dysregulation, in the development of the atrial arrhythmogenic substrate. Finally, we review the available therapeutic strategies to treat AF in the context of thyroid disease.

Atrial fibrillation in a patient with lung cancer: a case report

Introduction. Cancer remains one of the most common causes of death in the world, second only to cardiovascular diseases. The use of novel chemotherapeutic and targeted agents has significantly improved the prognosis of this group of patients. However, this significantly increased the number of cardiotoxic complications of anticancer therapy, including arrhythmias, in particular atrial fibrillation (AF), which negatively affects the prognosis.Brief description. The purpose of this article was to describe the case of a 64-yearold woman with central right lung lower lobe cancer. Upon admission to the chemotherapy department, the patient was first diagnosed with paroxysmal AF. After chemical cardioversion, the first course of multiagent chemotherapy (MAC) was performed as follows: paclitaxel 280 mg and carboplatin 450 mg, which was complicated by the development of recurrent AF episode. During subsequent MAC courses, arrhythmia episodes regularly occurred. During the next AF episode, the patient was hospitalized at the City Clinical Hospital № 51, where she died despite intensive therapy. Postmortem examination ruled out tumor invasion into the left atrium.Discussion. For the AF development, the patient had prerequisites in the form of a significantly remodeled left atrial myocardium. Chemotherapy agents used as antitumor therapy are characterized by the common development of cardiotoxicity, including variety of arrhythmias. The occurrence of AF episodes coincided with the course of MAC, which suggested its cardiotoxic manifestations. Postmortem examination confirmed the high probability of an association between AF episodes and MAC.Conclusion. The presented case illustrates the difficulties encountered by oncologists and cardiologists in determining the genesis and treatment of complex arrhythmias in cancer patients.

The Slow Force Response and Simultaneous Changes in Ca2+ Transient in Healthy and Failing Rat Atrial and Ventricular Myocardium

The Slow Force Response and Simultaneous Changes in Ca2+ Transient in Healthy and Failing Rat Atrial and Ventricular Myocardium

Functional effects of class I-selective HDAC-inhibition on human atrial myocardium

Functional effects of class I-selective HDAC-inhibition on human atrial myocardium

Morphological and histological study of coronary sinus in human hearts from north-western region of Uttar Pradesh and its clinical implication

Background: Coronary sinus (CS) is the largest diameter vessel in the coronary venous network, which serves as the primary collector of cardiac venous blood. Because the coronary venous system is not prone to the effects of atherosclerotic disease, it may also serve as a potential avenue for coronary artery bypass. Aims and Objectives: The aim of the study was to provide morphological and histological data of CS for making an interventional device. Materials and Methods: The present study cross-sectional study. Thirty hearts of different ages and of both sexes (22 males and 8 females) and duration of study is 2 years procured from cadavers available in the Department of Anatomy, SRMS IMS, Bareilly, U.P, India, were taken. Results: The mean length of the CS is 36.83±17.29 mm. The width of CS at the point of opening in to right atrium is 4.92±3.53 mm. The mean length of CS in males was 41.44±11.37 mm. While in females the mean length of CS was 39.29±11.17 mm. Histological study by Orcein stain show different amount of elastic fibers in proximal, middle, and distal part. Conclusion: Morphological and histological study of the CS suggests this structure to be an independent, cardiac chamber with a mural structure similar to atrial myocardium and it may be target for study and ablation, in the future therapy of atrial arrhythmias.

Bone morphogenetic protein 10: a novel risk marker of ischaemic stroke in patients with atrial fibrillation.

Biomarkers specifically related to atrial tissue may increase the understanding of the pathophysiology of atrial fibrillation (AF) and further improve risk prediction in this setting. Bone morphogenetic protein 10 (BMP10) is a protein expressed in the atrial myocardium. We evaluated the association between BMP10 and the risk of ischaemic stroke and other cardiovascular events in large cohorts of patients with AF, treated with and without oral anticoagulation (OAC). BMP10 was measured in plasma samples collected at randomisation in patients with AF without OAC in the ACTIVE A and AVERROES trials (n = 2974), and with OAC in the ARISTOTLE trial (n = 13 079). BMP10 was analysed with a prototype Elecsys immunoassay. Associations with outcomes were evaluated by Cox-regression models adjusted for clinical characteristics, kidney function, and N-terminal pro-B-type natriuretic peptide (NT-proBNP). Median concentrations of BMP10 were 2.47 and 2.44 ng/mL, in the non-OAC and OAC cohort, respectively. Increasing BMP10 was associated with lower body mass index, older age, female sex, kidney dysfunction, and AF rhythm. BMP10 was consistently associated with ischaemic stroke. In the non-OAC cohort, BMP10 increased the concordance index of the multivariable model from 0.713 to 0.733 (P = 0.004) and in the OAC cohort from 0.673 to 0.694 (P < 0.001). Additionally, BMP10 maintained a significant prognostic value after additionally adjusting for NT-proBNP. BMP10 was not independently associated with bleeding or with death. The novel atrial biomarker BMP10 was independently associated with ischaemic stroke in patients with AF irrespective of OAC treatment. BMP10 seems to be more specifically related to the risk of ischaemic stroke in AF. In this study, BMP10 may be a novel specific biomarker of ischaemic stroke in patients with atrial fibrillation, irrespective of oral anticoagulation.

Abstract 14782: Expression of Ngf Shrna in the Left Atrial Appendage Alone is Sufficient to Attenuate Global Left Atrial Parasympathetic and Sympathetic Nerve Sprouting and Resulting Development of Persistent Atrial Fibrillation in a Canine Model

Introduction: The autonomic nervous system plays a major role in development of atrial fibrillation (AF), with evidence of marked autonomic remodeling in a canine rapid atrial pacing (RAP) model of AF. Nerve growth factor (NGF), a neurotrophin essential for peripheral neuron growth, was upregulated in fibrillating atria, particularly in the left atrial appendage (LAA). Hypothesis: Inhibiting NGF signaling in the entire atria or the LAA alone can prevent the development of AF. Methods: NGF shRNA was injected in both atria or in the LAA of dogs followed by electroporation to facilitate gene delivery. Animals were subjected to RAP for up to 12 weeks. Duration of AF was recorded. At terminal EP study, residual AF electrograms were recorded in the posterior left atrium, left atrial free wall and LAA for analysis of AF characteristics. Tissue of each region was used for IHC with markers for parasympathetic (acetylcholinesterase) or sympathetic nerves (dopamine beta-hydroxylase). Results: Controls (n=10) developed persistent AF (&gt;8 hours) after a median of 14 days. In contrast, pan-atrial NGF shRNA animals (n=4) never developed this burden of AF. Residual AF was less fractionated (longer fractionation interval), more organized (higher organization index and lower Shannon's entropy) and more homogeneous (coefficient of variation of dominant frequency). RAP-induced nerve bundle hypertrophy and atrial myocardium hyperinnervation was significantly attenuated in pan-atrial NGF shRNA dogs. Importantly, these findings were reproduced when NGF shRNA injection was limited to the LAA alone (n=4), with prevention of development of persistent AF, and global attenuation of left atrial hyperinnervation. Conclusion: Targeted inhibition of atrial autonomic remodeling by NGF shRNA prevents development of persistent AF. NGF Inhibition in the LAA alone is sufficient to attenuate global atrial autonomic remodeling. This approach may lead to a novel, mechanism-guided therapy for AF.

Abstract 14906: Impact of Time Between Stacked Lesions During Radiofrequency Atrial Ablation With Active Esophageal Cooling

Background: Active esophageal cooling during radiofrequency (RF) ablation of the left atrium (LA) has been shown to reduce esophageal injury. Although no atrioesophageal fistula has been reported in over 12 thousand uses to date, the first pericardio-esophageal fistula to occur despite cooling reinforces the fact that a threshold may exist at which heat extraction capacity may be surpassed. We aimed to examine this threshold by measuring the transmurality of esophageal injury after sequential lesion placement. Hypothesis: Reduced rest time between stacked lesions increases tissue lesion depth by enhancing thermal latency effects. Methods: Using a computational model of the left atrium, we determined esophageal lesion depth between sequentially placed RF lesions using high-power, short duration power settings (50 W for 10 s). Lesion depth was determined via Arrhenius equation, and anatomical dimensions were:1.5 mm for atrial myocardium, 0.75 mm for pericardial tissue, and 2 mm for the esophagus. Three lesions were placed on the myocardium with either 5 s or 10 s pauses in between. Final lesion transmurality was measured 45 s after the last placement to fully account for latent heating. Results: Active esophageal cooling reduced esophageal lesion transmurality by 80% after the first lesion. Sequential lesions increased esophageal lesion transmurality, with thermal latency contributing to increased lesion depth even after cessation of RF energy. Shorter timing between lesions allowed further growth in transmurality: 4% for 90 W, and 8.5% for 50 W power settings (Figure 1), showing that the efficacy of cooling against thermal latency effects decreased with the placement of each subsequent lesion. Conclusions: Active esophageal cooling reduces esophageal lesion transmurality by 80% when single lesions are placed. Stacking additional lesions at the same point reduces this safety benefit, with shorter intervals between lesions resulting in less protective effect.

Low-Voltage Myocardium-Guided Ablation Trial of Persistent Atrial Fibrillation

BackgroundClinically effective ablation approaches for patients with persistent atrial fibrillation (AF) are still being debated. So far, ablation targets and strategies beyond pulmonary vein isolation (PVI) have failed to show systematic outcome improvement in randomized controlled clinical trials.MethodsWe conducted a multicenter, randomized trial to determine whether PVI plus individualized substrate ablation of atrial low-voltage myocardium improves outcome in patients with persistent AF. We randomly assigned 324 patients in a 1:1 ratio to receive PVI alone (163 patients; PVI only) or PVI plus substrate modification (161 patients; PVI+SM). The primary study end point was the first recurrence of an atrial arrhythmia longer than 30 seconds after single ablation, with 3 months blanking, using serial 7-day electrocardiogram recordings over 12 months of observation. Patients were also encouraged to receive implantable cardiac monitors.ResultsThe primary study end point occurred in 75 PVI-only patients (50%) and in 54 PVI+SM patients (35%) (Kaplan–Meier event rate estimates: hazard ratio=0.62, 95% confidence interval [CI]=0.43 to 0.88, log rank P=0.006). Adverse events occurred in three PVI-only patients (1.8%) and in six PVI+SM patients (3.7%) (difference: −1.9 percentage points, 95% CI=−5.5 to 1.7 percentage points). Implant monitoring was used in 242 patients. Among them, 65 PVI-only patients (55%) versus 47 PVI+SM patients (39%) experienced recurrences (difference: 15 percentage points, 95% CI=3 to 28 percentage points).ConclusionsIn this randomized trial, PVI plus individualized ablation of atrial low-voltage myocardium significantly improved outcomes in patients with persistent AF. (ClinicalTrials.gov number, NCT02732626.)