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This article reviews cardiac anatomy as it pertains to commonly used intracardiac echocardiography segments and views., Competing Interests: Disclosure None., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Bilateral cardiac sympathetic denervation (BCSD) is a surgical treatment for refractory ventricular arrhythmias. Although the procedure has shown efficacy at reducing cardiac arrhythmias, its impact on mental health is unknown. In the current study we examined associations between the BCSD procedure and mental health., Methods: 10 ventricular arrhythmia patients undergoing BCSD completed assessments of anxiety, depression, and posttraumatic stress symptoms at pre- and post-BCSD time points. Wilcoxon signed rank and Mann-Whitney U tests were used to examine differences in mental health symptoms in the pre- and post-BSCD states. Point biserial correlations were used to explore associations between BCSD response and mental health symptoms., Results: A significant reduction of anxiety symptoms was observed from pre- to post-BCSD. At the post-BCSD assessment, participants who successfully responded to the BCSD procedure exhibited lower anxiety symptoms compared to non-responders. However, no significant relationships were identified for depressive or PTSD symptoms., Conclusion: The BCSD procedure is associated with reduced anxiety shortly after successful treatment for refractory ventricular arrhythmias in a small sample. Longitudinal surveillance of mental health symptoms after BCSD may be warranted to monitor the impact of this procedure on mental health., (Copyright © 2021 Elsevier B.V. All rights reserved.)

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Importance: In patients with mechanical valves in the aortic and mitral positions, percutaneous access to the left ventricle (LV) via a transfemoral approach for catheter ablation of ventricular tachycardia (VT) has been considered infeasible., Objective: To describe the outcomes of a novel percutaneous trans-right atrial (RA) access to the LV via a femoral venous approach for catheter ablation of VT in patients with mechanical aortic and mitral valves., Design, Setting, and Participants: This observational study included consecutive patients with mechanical valves in the aortic and mitral positions and recurrent monomorphic drug-refractory VT associated with an LV substrate. Percutaneous LV access was performed from a transfemoral venous route with the aid of a deflectable sheath and a radiofrequency wire by creating an iatrogenic Gerbode defect with direct puncture of the inferior and medial aspect of the RA, adjacent to the inferior-septal process of the LV (ISP-LV), under intracardiac echography guidance. Once the wire crossed to the LV, balloon dilatation of the ventriculotomy site (with a noncompliant balloon; diameter, 8 to 10 mm) was performed to facilitate passage of the sheath within the LV., Exposures: Percutaneous trans-RA access to the LV via puncture of the ISP-LV to perform catheter ablation of VT in patients with mechanical aortic and mitral valves., Main Outcomes and Measures: Feasibility and safety of a trans-RA access to the LV for catheter ablation of VT., Results: A total of 4 patients (mean [SD] age, 60 [7] years; mean [SD] LV ejection fraction, 31% [9%]) with recurrent VT associated with an LV substrate (ischemic cardiomyopathy, 3 patients; nonischemic cardiomyopathy, 1 patient) and mechanical valves in the aortic and mitral position underwent trans-RA access through the ISP-LV for catheter ablation of VT. The time to obtain LV access ranged from 60 minutes (first case) to 22 minutes (last case) (mean [SD], 36 [15] minutes). No complications associated with the access occurred. In particular, in the 3 patients with preserved atrioventricular conduction at baseline, no new conduction abnormalities were observed after the access. Complete VT noninducibility at programmed ventricular stimulation was achieved in 3 cases, and no patient had VT recurrence at a median follow-up of 14 months (range, 6-21 months)., Conclusions and Relevance: A percutaneous trans-RA access to the LV via a femoral venous approach for catheter ablation of VT in patients with mechanical aortic and mitral valves is feasible and appears safe. This novel technique may allow for catheter ablation of VT in a population of patients in whom conventional LV access via retrograde aortic or atrial transseptal routes is not possible.

Vagus nerve stimulation has shown many benefits for disease therapies but current approaches involve imprecise electrical stimulation that gives rise to off-target effects, while the functionally relevant pathways remain poorly understood. One method to overcome these limitations is the use of optogenetic techniques, which facilitate targeted neural communication with light-sensitive actuators (opsins) and can be targeted to organs of interest based on the location of viral delivery. Here, we tested whether retrograde adeno-associated virus (rAAV2-retro) injected in the heart can be used to selectively express opsins in vagus nerve fibers controlling cardiac function. Furthermore, we investigated whether perturbations in cardiac function could be achieved with photostimulation at the cervical vagus nerve. Viral injection in the heart resulted in robust, primarily afferent, opsin reporter expression in the vagus nerve, nodose ganglion, and brainstem. Photostimulation using both one-photon stimulation and two-photon holography with a GRIN-lens incorporated nerve cuff, was tested on the pilot-cohort of injected mice. Changes in heart rate, surface electrocardiogram, and respiratory responses were observed in response to both one- and two-photon photostimulation. The results demonstrate feasibility of retrograde labeling for organ targeted optical neuromodulation.

Introduction: Patients with prior cardiac surgery may represent a subgroup of patients with ventricular tachycardia (VT) that may be more difficult to control with catheter ablation., Methods: We evaluated 1901 patients with ischemic and nonischemic cardiomyopathy who underwent VT ablation at 12 centers. Clinical characteristics and VT radiofrequency ablation procedural outcomes were assessed and compared between those with and without prior cardiac surgery. Kaplan-Meier analysis was used to estimate freedom from recurrent VT and survival., Results: There were 578 subjects (30.4%) with prior cardiac surgery identified in the cohort. Those with prior cardiac surgery were older (66.4 ± 11.0 years vs. 60.5 ± 13.9 years, p < .01), with lower left ventricular ejection fraction (30.2 ± 11.5% vs. 34.8 ± 13.6%, p < .01) and more ischemic heart disease (82.5% vs. 39.3%, p < .01) but less likely to undergo epicardial mapping or ablation (9.0% vs. 38.1%, p<.01) compared to those without prior surgery. When epicardial mapping was performed, a significantly greater proportion required surgical intervention for access (19/52 [36.5%] vs. 14/504 [2.8%]; p < .01). Procedural complications, including epicardial access-related complications, were lower (5.7% vs. 7.0%, p < .01) in patients with versus without prior cardiac surgery. VT-free survival (75.1% vs. 74.1%, p = .805) and survival (86.5% vs. 87.9%, p = .397) were not different between those with and without prior heart surgery, regardless of etiology of cardiomyopathy. VT recurrence was associated with increased mortality in patients with and without prior cardiac surgery., Conclusion: Despite different clinical characteristics and fewer epicardial procedures, the safety and efficacy of VT ablation in patients with prior cardiac surgery is similar to others in this cohort. The incremental yield of epicardial mapping in predominant ischemic cardiomyopathy population prior heart surgery may be low but appears safe in experienced centers., (© 2020 Wiley Periodicals LLC.)

Background Cardiac sympathetic denervation (CSD) has been used as a bailout strategy for refractory ventricular tachycardia (VT). Risk of VT recurrence in patients with scar-related monomorphic VT referred for CSD and the extent to which CSD can modify this risk is unknown. We aimed to quantify arrhythmia recurrence risk and impact of CSD in this population. Methods and Results Adjusted competing risk time to event models were developed to adjust for risk of VT recurrence and sustained VT/implantable cardioverter-defibrillator shocks after VT ablation based on patient comorbidities at the time of VT ablation. Adjusted VT and implantable cardioverter-defibrillator shock recurrence rates were estimated for the subgroup who subsequently required CSD after ablation. The expected adjusted recurrence rates were then compared with the observed rates after CSD. Data from 381 patients with scar-mediated monomorphic VT who underwent VT ablation were analyzed, excluding patients with polymorphic VT. Sixty eight patients underwent CSD for recurrent VT. CSD reduced the expected adjusted VT recurrence rate by 36% (expected rate of 5.61 versus observed rate of 3.58 per 100 person-months, P =0.01) and the sustained VT/implantable cardioverter-defibrillator shock rates by 34% (expected rate of 4.34 versus observed 2.85 per 100 person-months, P =0.03). The median number of sustained VT/implantable cardioverter-defibrillator shocks in the year before versus the year after CSD was reduced by 90% (10 versus 1, P <0.0001). Conclusions Patients referred for CSD for refractory scar-mediated monomorphic VT are at a higher risk of VT recurrence after ablation as compared with those not requiring CSD, mostly because of their cardiac comorbidities. CSD significantly reduced both the expected risk of recurrences and VT burden.

Sympathetic control of regional cardiac function occurs through postganglionic innervation from stellate ganglia and thoracic sympathetic chain. Whereas norepinephrine (NE) is their primary neurotransmitter, neuropeptide Y (NPY) is an abundant cardiac cotransmitter. NPY plays a vital role in homeostatic processes including angiogenesis, vasoconstriction, and cardiac remodeling. Elevated sympathetic stress, resulting in increased NE and NPY release, has been implicated in the pathogenesis of several cardiovascular disorders including hypertension, myocardial infarction, heart failure, and arrhythmias, which may result in sudden cardiac death. Current methods for the detection of NPY in myocardium are limited in their spatial and temporal resolution and take days to weeks to provide results [e.g., interstitial microdialysis with subsequent analysis by enzyme-linked immunosorbent assay (ELISA), high performance liquid chromatography (HPLC), or mass spectrometry]. In this study, we report a novel approach for measurement of interstitial and intravascular NPY using a minimally invasive capacitive immunoprobe (C.I. probe). The first high-spatial and temporal resolution, multichannel measurements of NPY release in vivo are provided in both myocardium and transcardiac vascular space in a beating porcine heart. We provide NPY responses evoked by sympathetic stimulation and ectopic ventricular pacing and compare these to NE release and hemodynamic responses. We extend this approach to measure both NPY and vasoactive intestinal peptide (VIP) and show differential release profiles under sympathetic stimulation. Our data demonstrate rapid and local changes in neurotransmitter profiles in response to sympathetic cardiac stressors. Future implementations include real-time intraoperative determination of cardiac neuropeptides and deployment as a minimally invasive catheter. NEW & NOTEWORTHY The sympathetic nervous system regulates cardiac function through release of neurotransmitters and neuropeptides within the myocardium. Neuropeptide Y (NPY) acts as an acute cardiac vasoconstrictor and chronically to regulate angiogenesis and cardiac remodeling. Current methodologies for the measure of NPY are not capable of providing rapid readouts on a single-sample basis. Here we provide the first in vivo methodology to report dynamic, localized NPY levels within both myocardium and vascular compartments in a beating heart.

The prevalence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) quickly reached pandemic proportions, and knowledge about this virus and coronavirus disease 2019 (COVID-19) has expanded rapidly. This review focuses primarily on mechanisms that contribute to acute cardiac injury and dysfunction, which are common in patients with severe disease. The etiology of cardiac injury is multifactorial, and the extent is likely enhanced by preexisting cardiovascular disease. Disruption of homeostatic mechanisms secondary to pulmonary pathology ranks high on the list, and there is growing evidence that direct infection of cardiac cells can occur. Angiotensin-converting enzyme 2 (ACE2) plays a central role in COVID-19 and is a necessary receptor for viral entry into human cells. ACE2 normally not only eliminates angiotensin II (Ang II) by converting it to Ang-(1-7) but also elicits a beneficial response profile counteracting that of Ang II. Molecular analyses of single nuclei from human hearts have shown that ACE2 is most highly expressed by pericytes. Given the important roles that pericytes have in the microvasculature, infection of these cells could compromise myocardial supply to meet metabolic demand. Furthermore, ACE2 activity is crucial for opposing adverse effects of locally generated Ang II, so virus-mediated internalization of ACE2 could exacerbate pathology by this mechanism. While the role of cardiac pericytes in acute heart injury by SARS-CoV-2 requires investigation, expression of ACE2 by these cells has broader implications for cardiac pathophysiology.

Aims: Catheter ablation is an effective treatment for post-infarction ventricular tachycardia (VT). However, some patients may experience a worsened arrhythmia phenotype after ablation. We aimed to determine the prevalence and prognostic impact of arrhythmia exacerbation (AE) after post-infarction VT ablation., Methods and Results: A total of 1187 consecutive patients (93% men, median age 68 years, median ejection fraction 30%) who underwent post-infarction VT ablation at six centres were included. Arrhythmia exacerbation was defined as post-ablation VT storm or incessant VT in patients without prior similar events. During follow-up (median 717 days), 426 (36%) patients experienced VT recurrence. Events qualifying as AE occurred in 67 patients (6%). Median times to VT recurrence with and without AE were 238 [interquartile range (IQR) 35-640] days and 135 (IQR 22-521) days, respectively (P = 0.25). Almost half of the patients (46%) who experienced AE experienced it within 6 months of the index procedure. Patients with AE had had longer ablation times during the ablation procedures compared to the rest of the patients (median 42 vs. 34 min, P = 0.02). Among patients with VT recurrence, the risk of death or heart transplantation was significantly higher in patients with than without AE (hazard ratio 1.99, 95% CI 1.28-3.10; P = 0.002) after adjusting for age, gender, ejection fraction, cardiac resynchronization therapy, post-ablation non-inducibility, and post-ablation amiodarone use., Conclusion: Arrhythmia exacerbation after ablation of infarct-related VT is infrequent but is independently associated with an adverse long-term outcome among patients who experience a VT recurrence. The mechanisms and mitigation strategies of AE after catheter ablation require further investigation., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: journals.permissions@oup.com.)

Objectives: This study sought to determine the relationship between long QT syndrome (LQTS) subtype (LTQ1, LTQ2, LTQ3) and postnatal cardiac events (CEs)., Background: LQTS presenting with 2:1 atrioventricular block or torsades de pointes in the fetus and/or neonate has been associated with risk for major CEs, but overall outcomes and predictors remain unknown., Methods: A retrospective study involving 25 international centers evaluated the course of fetuses/newborns diagnosed with congenital LQTS and either 2:1 atrioventricular block or torsades de pointes. The primary outcomes were age at first CE after dismissal from the newborn hospitalization and death and/or cardiac transplantation during follow-up. CE was defined as aborted cardiac arrest, appropriate shock from implantable cardioverter-defibrillator, or sudden cardiac death., Results: A total of 84 fetuses and/or neonates were identified with LQTS (12 as LQT1, 35 as LQT2, 37 as LQT3). Median gestational age at delivery was 37 weeks (interquartile range: 35 to 39 weeks) and age at hospital discharge was 3 weeks (interquartile range: 2 to 5 weeks). Fetal demise occurred in 2 and pre-discharge death in 1. Over a median of 5.2 years, there were 1 LQT1, 3 LQT2, and 23 LQT3 CEs (13 aborted cardiac arrests, 5 sudden cardiac deaths, and 9 appropriate shocks). One patient with LQT1 and 11 patients with LQT3 died or received cardiac transplant during follow-up. The only multivariate predictor of post-discharge CEs was LQT3 status (LQT3 vs. LQT2: hazard ratio: 8.4; 95% confidence interval: 2.6 to 38.9; p < 0.001), and LQT3, relative to LQT2, genotype predicted death and/or cardiac transplant (p < 0.001)., Conclusions: In this large multicenter study, fetuses and/or neonates with LQT3 but not those with LQT1 or LQT2 presenting with severe arrhythmias were at high risk of not only frequent, but lethal CEs., Competing Interests: Author Relationship With Industry Dr. Strasburger has received support from the National Institutes of Health grant RO1HL143485. Dr. Wakai has received support from the National Institutes of Health grant RO1HL063174. Dr. Miyake has received support from the National Heart, Lung, and Blood Institute grant K23HL136932 and American Heart Association grant 17SDG33410183. Dr. Schwartz has received support from the National Institutes of Health grant HL083374 and Italian Ministry of Health grant (Sindrome della morte improvvisa del lattante: meccanismi e prevenzione). All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Published by Elsevier Inc.)

Introduction: Cardiac sympathetic denervation (CSD) is utilized for the management of ventricular tachycardia (VT) in structural heart disease when refractory to radiofrequency ablation (RFA) or when patient/VT characteristics are not conducive to RFA., Methods: We studied consecutive patients who underwent CSD at our institution from 2009 to 2018 with VT requiring repeat RFA post-CSD. Patient demographics, VT/procedural characteristics, and outcomes were assessed., Results: Ninety-six patients had CSD, 16 patients underwent RFA for VT post-CSD. There were 15 male and 1 female patients with mean age of 54.2 ± 13.2 years. Fourteen patients had nonischemic cardiomyopathy. A mean of 2.0 ± 0.8 RFAs for VT was unsuccessful before the patient undergoing CSD. The median time between CSD and RFA was 104 days (interquartile range [IQR] = 15-241). The clinical VT cycle length was significantly increased after CSD both spontaneously on ECG and/or ICD interrogation (355 ± 73 ms pre-CSD vs. 422 ± 94 ms post-CSD, p = .001) and intraprocedurally (406 ± 86 ms pre-CSD vs. 457 ± 88 ms post-CSD, p = .03). Two patients had polymorphic and 14 had monomorphic VT (MMVT) pre-CSD, and all patients had MMVT post-CSD. The proportion of mappable, hemodynamically stable VTs increased from 35% during pre-CSD RFA to 58% during post-CSD RFA (p = .038). At median follow-up of 413 days (IQR = 43-1840) after RFA, eight patients had no further VT., Conclusion: RFA for recurrent MMVT post-CSD is a reasonable treatment option with intermediate-term clinical success in 50% of patients. Clinical VT cycle length was significantly increased after CSD with associated improvement in mappable, hemodynamically tolerated VT during RFA., (© 2020 Wiley Periodicals LLC.)

The pericardial cavity and its boundaries are formed by the reflections of the visceral and parietal pericardial layers. This space is an integral access point for epicardial interventions. As the pericardial layers reflect over the great vessels and the heart, they form sinuses and recesses, which restrict catheter movement. The epicardial vasculature is also important when performing nearby catheter ablation. The phrenic nerve and esophagus are other important structures to appreciate so as to avoid collateral injury. In addition, the Larrey space, or left sternocostal triangle, is a key avascular window through which pericardial access can be safely achieved., Competing Interests: Disclosure None., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Managing arrhythmias from the left ventricular summit and interventricular septum is a major challenge for the clinical electrophysiologist requiring intimate knowledge of cardiac anatomy, advanced training and expertise. Novel mapping and ablation strategies are needed to treat arrhythmias originating from these regions given the current suboptimal long-term success rates with standard techniques. Herein, we describe innovative approaches to improve acute and long-term clinical outcomes such as mapping and ablation using the septal coronary venous system and the septal coronary arteries, alcohol ablation, coil embolization, and ablation of all early sites among others., (Copyright © 2020 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

The long QT syndrome (LQTS) is largely treated pharmacologically with β-blockers, despite the role of sympathetic activity in LQTS being poorly understood. Using the trigger-substrate model of cardiac arrhythmias in this review, we amalgamate current experimental and clinical data from both animal and human studies to explain the mechanism of adrenergic stimulation and blockade on LQT arrhythmic risk and hence assess the efficacy of β-adrenoceptor blockade in the management of LQTS. In LQTS1 and LQTS2, sympathetic stimulation increases arrhythmic risk by enhancing early afterdepolarizations and transmural dispersion of repolarization. β-Blockers successfully reduce cardiac events by reducing these triggers and substrates; however, these effects are less marked in LQTS2 compared with LQTS1. In LQTS3, clinical and experimental investigations of the effects of sympathetic stimulation and β-blocker use have produced contradictory findings, resulting in significant clinical uncertainty. We offer explanations for these contradicting results relating to study sample size, the dose of the β-blocker administered associated with its off-target Na + channel effects, as well as the type of β-blocker used. We conclude that the antiarrhythmic efficacy of β-blockers is a genotype-specific phenomenon, and hence the use of β-blockers in clinical practice should be genotype dependent., (© 2020 The Authors. Annals of the New York Academy of Sciences published by Wiley Periodicals LLC on behalf of New York Academy of Sciences.)

Background: Computed tomography (CT) is used for the diagnosis of cardiac perforation (CP) although it has significant limitations. We report our experience with angiography to assist in the diagnosis and management of cardiac perforation during electrophysiology procedures., Methods: Patients with suspected CP after pacemaker lead insertion (temporary = 2, permanent = 2) or during epicardial mapping/ablation (n = 2) were included. All patients underwent initial angiography with repeat study performed post-lead repositioning/withdrawal for the pacemaker cases. Patients with CP due to permanent pacing leads underwent CT comparison., Results: In 4 pacemaker patients, temporary leads caused two acute perforations, permanent active fixation leads caused one subacute right ventricular perforation and one delayed right atrial perforation. CT overdiagnosed CP in one temporary pacemaker patient, and was non-diagnostic in an atrial lead perforation, whereas angiography was accurate in both. Angiography identified an active leak in atrial lead CP, guided percutaneous closure in one case and demonstrated sealing of perforation in all cases. In the 2 epicardial ablation cases, 1 patient underwent surgical repair after a persistent right ventricular perforation, but the other avoided surgery with novel use of an Amplazter® patent ductus arteriosus (PDA) closure device (Abbott, St Paul, MN, USA)., Conclusions: Angiography may be more accurate than CT in the diagnosis of CP. Angiography is easy to perform, can be done acutely, reveals active leaks and can demonstrate sealing of perforations after percutaneous lead repositioning. Utilisation of a PDA closure device may avoid the need for surgery for RV perforation.

Background: Bilateral cardiac sympathetic denervation (BCSD) is an effective therapy for ventricular arrhythmias (VAs) in cardiomyopathies (CMPs). After BCSD, residual autonomic nervous system (ANS) function is unknown., Objective: The purpose of this study was to assess ANS responses in patients with CMP before and after BCSD as compared with demographically matched healthy controls., Methods: Patients with CMP undergoing BCSD and matched healthy controls were recruited. Noninvasive measures-finger cuff beat-to-beat blood pressure (BP), electrocardiography, palmar electrodermal activity (EDA), and finger pulse volume (FPV)-were obtained at rest and during autonomic stressors-posture change, handgrip, and mental stress. Maximal as well as specific responses to stressors were compared., Results: Eighteen patients with CMP (mean age 54 ± 14 years; 16 men, 89%; left ventricular ejection fraction 36% ± 14%) with refractory VAs and 8 matched healthy controls were studied; 9 patients with CMP underwent testing before and after (median 28 days) BCSD, with comparable ongoing medication. Before BCSD, patients with CMP (n = 13) had lower resting systolic BP and FPV than did healthy controls (P < .01). Maximal FPV and systolic BP reflex responses, expressed as percent change were similar, while diastolic BP, mean BP, and EDA responses were blunted. After BCSD, resting measurements were unchanged relative to presurgical baseline (n = 9). EDA responses to stressors were abolished, confirming BCSD, while maximal FPV and BP responses were preserved. Diastolic BP, mean BP, and FPV responses to orthostatic challenge pointed toward a better tolerance of active standing after BCSD as compared with before. Responses to other stressors remained unchanged., Conclusion: Patients with CMP and refractory VAs on optimal medical therapy have detectable but blunted adrenergic responses, which are not disrupted by BCSD., (Copyright © 2020 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Background: We aimed to develop a risk score (LGE Based Prediction of SCD Risk in Nonischemic Dilated Cardiomyopathy [ESTIMATED]) based on late gadolinium enhancement (LGE) cardiac magnetic resonance to predict sudden cardiac death (SCD) in patients with nonischemic dilated cardiomyopathy (NIDCM) and left ventricular ejection fraction ≤ 35%., Methods: We recruited 395 consecutive middle-aged patients with NIDCM and performed 3-year follow-up for SCD events. The score was developed and verified in 295 primary prevention patients, and the predictive value was confirmed by comparing the SCD events between the high-risk patients stratified by the score and 100 secondary prevention patients., Results: The ESTIMATED score (constructed by the LGE extent > 14%, syncope, atrial flutter/fibrillation, nonsustained ventricular tachycardia, advanced atrioventricular block, and age ≤ 20 or > 50 years) showed good calibrations for SCD prediction in the derivation (C-statistic: 0.80, 95% confidence interval: 0.74-0.86) and validation set (C-statistic: 0.80, 95% confidence interval: 0.71-0.87). By the score, 20.3% of primary prevention patients were categorized as high risk (≥ 3 points), 28.1% as intermediate risk (2 points), and 51.6% as low risk (0-1 points) for 3-year SCD events (45.9% vs 20.1% vs 5.1%, P < 0.0001). The 3-year SCD events were also well in agreement with the score stratification in patients without implantable cardioverter-defibrillator. High-risk primary prevention patients selected by the score in the derivation and validation sets had 3-year SCD events comparable with that in secondary prevention patients (47.6% vs 40.6% vs 38.7%, P = 0.81)., Conclusions: Our study derived and validated an LGE-based (ESTIMATED) risk score providing refined SCD prediction. The score may help to identify candidates for primary prevention implantable cardioverter-defibrillator in patients with NIDCM., (Copyright © 2020 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.)

Aims: ST-elevation myocardial infarction is associated with high levels of cardiac sympathetic drive and release of the co-transmitter neuropeptide Y (NPY). We hypothesized that despite beta-blockade, NPY promotes arrhythmogenesis via ventricular myocyte receptors., Methods and Results: In 78 patients treated with primary percutaneous coronary intervention, sustained ventricular tachycardia (VT) or fibrillation (VF) occurred in 6 (7.7%) within 48 h. These patients had significantly (P < 0.05) higher venous NPY levels despite the absence of classical risk factors including late presentation, larger infarct size, and beta-blocker usage. Receiver operating curve identified an NPY threshold of 27.3 pg/mL with a sensitivity of 0.83 and a specificity of 0.71. RT-qPCR demonstrated the presence of NPY mRNA in both human and rat stellate ganglia. In the isolated Langendorff perfused rat heart, prolonged (10 Hz, 2 min) stimulation of the stellate ganglia caused significant NPY release. Despite maximal beta-blockade with metoprolol (10 μmol/L), optical mapping of ventricular voltage and calcium (using RH237 and Rhod2) demonstrated an increase in magnitude and shortening in duration of the calcium transient and a significant lowering of ventricular fibrillation threshold. These effects were prevented by the Y1 receptor antagonist BIBO3304 (1 μmol/L). Neuropeptide Y (250 nmol/L) significantly increased the incidence of VT/VF (60% vs. 10%) during experimental ST-elevation ischaemia and reperfusion compared to control, and this could also be prevented by BIBO3304., Conclusions: The co-transmitter NPY is released during sympathetic stimulation and acts as a novel arrhythmic trigger. Drugs inhibiting the Y1 receptor work synergistically with beta-blockade as a new anti-arrhythmic therapy., (© The Author(s) 2019. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Aim: The role of the right ventricle (RV) in pulseless electrical activity (PEA) is poorly defined outside of pulmonary embolism. We aimed to (1) describe the continuous electrocardiographic (ECG) manifestations of RV strain (RVS) preceding PEA/Asystole in-hospital cardiac arrest (IHCA), and (2) determine the prevalence and clinical causes of RVS in PEA/Asystole IHCA., Methods: In this retrospective cross-sectional study, we evaluated 140 patients with continuous ECG data preceding PEA/Asystole IHCA. We iteratively defined the RVS continuous ECG pattern using the development cohort (93 patients). Clinical cause determination was blinded from ECG analysis in the validation cohort (47 patients)., Results: The overall cohort had mean age 62.1 ± 17.1 years, 70% return of spontaneous circulation and 30% survival to discharge. RVS continuous ECG pattern was defined as progressive RV depolarization delay in lead V1 with at least one supporting finding of RV ischaemia or right axis deviation. Using this criterion, 66/140 (47%) cases showed preceding RVS. In patients with RVS, no pulmonary embolism was found in 9/13 (69%) autopsies and 8/10 (80%) CT chest angiograms. The positive and negative predictive value of RVS pattern for diagnosing a respiratory cause of PEA/Asystole in the validation cohort was 81% [95% CI 64-98%] and 58% [95% CI 36-81%], respectively., Conclusion: RVS continuous ECG pattern preceded 47% of PEA/Asystole IHCA and is predictive of a respiratory cause of cardiac arrest, not just pulmonary embolism. These suggest that rapid elevations in pulmonary pressures and resultant RV failure may cause PEA in respiratory failure., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: Dispersion in ventricular repolarization is relevant for arrhythmogenesis., Objective: The purpose of this study was to determine the spatiotemporal effects of sympathetic stimulation on ventricular repolarization., Methods: In 5 anesthetized female open-chest pigs, ventricular repolarization was measured from the anterior, lateral, and posterior walls of the left ventricle (LV) and right ventricle using up to 40 transmural plunge needles (4 electrodes each) before and after left stellate ganglion stimulation (LSGS) and right stellate ganglion stimulation. In addition, LSGS was performed in 3 pigs (2 male, 1 female) before and after verapamil (5-10 mg/h) administration., Results: LSGS yielded a biphasic response in repolarization in the lateral and posterior walls of the LV, with prolongation at ∼5 seconds (10 ± 1.5 ms) and shortening at 20-30 seconds of stimulation (-28.9 ± 4.4 ms) during a monotonic pressure increase. While the initial prolongation was abolished by verapamil, late shortening was augmented. Sequential transections of the vagal nerve and stellate ganglia augmented repolarization dispersion responses to LSGS in 2 of 5 hearts. An equal pressure increase by aortic occlusion resulted in a homogeneous shortening of repolarization in the LV, and the effects were smaller than those during LSGS. Right stellate stimulation shortened repolarization mainly in the anterior LV wall, but the effects were smaller than those of LSGS., Conclusion: LSGS first prolongs (through the L-type calcium current) and then shortens repolarization. The effect of LSGS was prominent in the posterior and lateral, not the anterior, LV walls., (Copyright © 2020. Published by Elsevier Inc.)

Background: Cardiac sympathetic denervation (CSD) is a promising treatment for patients with structural heart disease (SHD) and refractory ventricular tachyarrhythmias (VTs). The effect of CSD on atrial rhythm as well as the prognostic impact of atrial arrhythmias (AAs) or left atrial volume index (LAVI) on CSD outcome are unknown., Objectives: The goals of this study were to evaluate the impact of AAs and LAVI on CSD outcome and to assess changes in AAs burden and in atrial pacing after CSD., Methods: Patients with SHD undergoing CSD for VTs were analyzed. Hazards models were built to assess predictors of sustained VT/implantable cardioverter-defibrillator (ICD) shock recurrences and death/orthotopic heart transplant (OHT). Changes before vs after CSD were assessed using ICD, clinical, and echocardiographic data. A drug index was devised to correct for medication use., Results: Between 2009 and 2018, 91 patients (mean age 56 ± 13 years; mean left ventricular ejection fraction 34% ± 14%; 47% with a history of AAs) underwent left CSD (16%) or bilateral CSD (BCSD). The median follow-up was 14 months (interquartile range 4-37 months). Using multivariable analysis, neither LAVI nor AAs were associated with recurrences; LAVI was an independent predictor of death/OHT. AAs burden did not change after BCSD, but atrial pacing increased from a median of 28% to 72% (P < .01). Left ventricular end-diastolic diameter slightly increased; however, sustained VT/ICD shocks were reduced., Conclusion: In patients with SHD undergoing CSD, LAVI predicts death/OHT. AAs burden, already low at baseline, was unchanged after BCSD, while the need for atrial pacing increased, suggesting an impact of BCSD on sinus node chronotropism., (Copyright © 2019 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

The sympathetic nervous system modulates cardiac function by controlling key parameters such as chronotropy and inotropy. Sympathetic control of ventricular function occurs through extrinsic innervation arising from the stellate ganglia and thoracic sympathetic chain. In the healthy heart, sympathetic release of norepinephrine (NE) results in positive modulation of chronotropy, inotropy, and dromotropy, significantly increasing cardiac output. However, in the setting of myocardial infarction or injury, sympathetic activation persists, contributing to heart failure and increasing the risk of arrhythmias, including sudden cardiac death. Methodologies for detection of norepinephrine in cardiac tissue are limited. Present techniques rely on microdialysis for analysis by high-performance liquid chromatography coupled to electrochemical detection (HPLC-ED), radioimmunoassay, or other immunoassays, such as enzyme-linked immunosorbent assay (ELISA). Although significant information about the release and action of norepinephrine has been obtained with these methodologies, they are limited in temporal resolution, require large sample volumes, and provide results with a significant delay after sample collection (hours to weeks). In this study, we report a novel approach for measurement of interstitial cardiac norepinephrine, using minimally invasive, electrode-based, fast-scanning cyclic voltammetry (FSCV) applied in a beating porcine heart. The first multispatial and high temporal resolution, multichannel measurements of NE release in vivo are provided. Our data demonstrate rapid changes in interstitial NE profiles with regional differences in response to coronary ischemia, sympathetic nerve stimulation, and alterations in preload/afterload. NEW & NOTEWORTHY Pharmacological, electrical, or surgical regulation of sympathetic neuronal control can be used to modulate cardiac function and treat arrhythmias. However, present methods for monitoring sympathetic release of norepinephrine in the heart are limited in spatial and temporal resolution. Here, we provide for the first time a methodology and demonstration of practice and rapid measures of individualized regional autonomic neurotransmitter levels in a beating heart. We show dynamic, spatially resolved release profiles under normal and pathological conditions.

Importance: Chronic heart failure (CHF) is associated with increased sympathetic drive and may increase expression of the cotransmitter neuropeptide Y (NPY) within sympathetic neurons., Objective: To determine whether myocardial NPY levels are associated with outcomes in patients with stable CHF., Design, Setting, and Participants: Prospective observational cohort study conducted at a single-center, tertiary care hospital. Stable patients with heart failure undergoing elective cardiac resynchronization therapy device implantation between 2013 and 2015., Main Outcomes and Measures: Chronic heart failure hospitalization, death, orthotopic heart transplantation, and ventricular assist device placement., Results: Coronary sinus (CS) blood samples were obtained during cardiac resynchronization therapy (CRT) device implantation in 105 patients (mean [SD] age 68 [12] years; 82 men [78%]; mean [SD] left ventricular ejection fraction [LVEF] 26% [7%]). Clinical, laboratory, and outcome data were collected prospectively. Stellate ganglia (SG) were collected from patients with CHF and control organ donors for molecular analysis. Mean (SD) CS NPY levels were 85.1 (31) pg/mL. On bivariate analyses, CS NPY levels were associated with estimated glomerular filtration rate (eGFR; rs = -0.36, P < .001); N-terminal-pro hormone brain natriuretic peptide (rs = 0.33; P = .004), and LV diastolic dimension (rs = -0.35; P < .001), but not age, LVEF, functional status, or CRT response. Adjusting for GFR, age, and LVEF, the hazard ratio for event-free (death, cardiac transplant, or left ventricular assist device) survival for CS NPY ≥ 130 pg/mL was 9.5 (95% CI, 2.92-30.5; P < .001). Immunohistochemistry demonstrated significantly reduced NPY protein (mean [SD], 13.7 [7.6] in the cardiomyopathy group vs 31.4 [3.7] in the control group; P < .001) in SG neurons from patients with CHF while quantitative polymerase chain reaction demonstrated similar mRNA levels compared with control individuals, suggesting increased release from SG neurons in patients with CHF., Conclusions and Relevance: The CS levels of NPY may be associated with outcomes in patients with stable CHF undergoing CRT irrespective of CRT response. Increased neuronal traffic and release may be the mechanism for elevated CS NPY levels in patients with CHF. Further studies are warranted to confirm these findings., Trial Registration: ClinicalTrials.gov identifier: NCT01949246.

Background: Autonomic modulation is finding an increasing role in the treatment of ventricular arrhythmias. Renal denervation (RDN) has been described as a treatment modality for refractory ventricular tachycardia (VT) in case series., Objective: The purpose of this study was to evaluate RDN as an adjunctive therapy to cardiac sympathetic denervation (CSD) for ablation refractory VT., Methods: Patients who underwent RDN after radiofrequency ablation and CSD procedures at our center from 2012 to 2019 were evaluated., Results: Ten patients underwent RDN after CSD (9 bilateral and 1 left-sided only) with a median follow-up of 23 months. The mean age was 59.9 ± 10.4 years, and 9/10 (90%) were men. All had cardiomyopathy with a mean ejection fraction of 33% ± 11% (20% ischemic). Four (40%) underwent CSD during the same hospitalization as that for RDN. Patients who underwent RDN as adjunctive therapy to CSD had a decrease in all implantable cardioverter-defibrillator therapies (shocks + antitachycardia pacing [ATP]) from 29.5 ± 25.2 to 7.1 ± 10.1 comparing 6 months pre-RDN to 6 months post-RDN (P = .028). Implantable cardioverter-defibrillator shocks were significantly decreased from 7.0 ± 6.1 to 1.7 ± 2.5 comparing 6 months pre-RDN to 6 months post-RDN (P = .026). This benefit was driven by a decrease in therapies for 6 patients who had a staged procedure, not performed during the same hospitalization (28.5 ± 24.3 to 1.0 ± 1.2; P = .043)., Conclusion: RDN demonstrates the potential benefit when VT recurs after radiofrequency ablation and CSD. The benefit is seen in patients who undergo a staged procedure. The need for acute RDN after CSD portends a poor prognosis., (Copyright © 2019 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

The purpose of this study was to define the mechanism by which cardiac neuraxial decentralization or spinal cord stimulation (SCS) reduces ischemia-induced ventricular fibrillation (VF). Direct measurements of norepinephrine (NE) levels in the left ventricular interstitial fluid (ISF) by microdialysis, in response to transient (15-minute) coronary artery occlusion (CAO), were performed in anesthetized canines. Responses were studied in animals with intact neuraxes and were compared with those in which the intrathoracic component of the cardiac neuraxes (stellate ganglia) or the intrinsic cardiac neuronal (ICN) system was surgically delinked from the central nervous system and those with intact neuraxes with preemptive SCS (T1-T3). With intact neuraxes, animals with exaggerated NE release due to CAO were at increased risk for VF. During CAO, there was a 152% increase in NE when the neuraxes were intact compared with 114% following stellate decentralization and 16% following ICN decentralization. During SCS, CAO NE levels increased by 59%. Risk for CAO-induced VF was 38% in controls, 8% following decentralization, and 11% following SCS. These data indicate that ischemia-related afferent neuronal transmission differentially engages central and intrathoracic sympathetic reflexes and amplifies sympathoexcitation. Differences in regional ventricular NE release are associated with increased risk for VF. Surgical decentralization or SCS reduced NE release and VF.

Access to the epicardial space is fundamental to several cardiac procedures. While traditional indications include catheter ablation of ventricular arrhythmias and accessory pathways, novel indications include left atrial appendage occlusion, esophageal protection, mapping and ablation during atrial fibrillation procedures, implantation of epicardial pacing leads, and phrenic nerve displacement to facilitate safe ablation of atrial and ventricular arrhythmias. Accessing the epicardial space safely is a major challenge requiring intimate knowledge of cardiac anatomy, extensive training, and expertise. Over the past years, multiple technological advances have led to significant improvements in epicardial access success and safety. Important examples of such advances include CO 2 insufflation through the coronary sinus or the right atrial appendage, pressure sensor needle, computed tomography, cardiac magnetic resonance, and electroanatomic mapping-guided epicardial access. In addition, we provide special maneuvers to minimize inadvertent right ventricular perforation., (Copyright © 2019 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Background: Cardiac sympathetic denervation (CSD) is an important adjunctive option for patients with refractory ventricular arrhythmias (VAs). Reports of efficacy of CSD in patients with structural heart disease (SHD) and refractory VA vary widely in literature., Objective: The purpose of this study was to conduct a systematic review of arrhythmic outcomes and complications in patients with SHD who underwent CSD due to recurrent VAs., Methods: Electronic databases (Google Scholar and PubMed) were searched to identify reports on CSD in SHD using appropriate medical subject terms. No sample size restriction was applied. All patients with known channelopathies were excluded. Baseline demographic and surgical data, arrhythmic outcomes, and procedural complications were evaluated., Results: A total of 13 studies and 173 patients were included. Of the 173 patients (121 [70%] male); pooled mean age 54.6 [95% confidence interval 52.6-56.7] years), 48 (28%) had ischemic cardiomyopathy, and 141 (82%) underwent bilateral CSD. Overall freedom from events ranged from 58% to 100%. Complications were reported in 49 patients(28%). Transient hypotension (9%), pneumothorax (5%), neuropathic pain (skin sensitivity) (4%), Horner syndrome (3%), sweating pattern changes (3%), and hemothorax (2%) were the most common complications. No procedure-related deaths were reported., Conclusion: CSD reduced the number of VA events in patients with SHD, and the benefit from the intervention seemed to be independent of the underlying SHD. Although overall rate of postprocedural complications was high, most of the complications were temporary. Major postprocedural complications after CSD were infrequent., (Copyright © 2019 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Background: Recurrences of atrial fibrillation (AF) after ablation have been attributed to conduction gaps and nontransmural ablation lesions., Objective: The purpose of this study was to assess the feasibility of adjunctive percutaneous mapping of the epicardial regions of the left atrium to characterize the transmural extent of substrate and ablation lesions., Methods: Between 2014 and 2018, combined epicardial and endocardial mapping of AF was performed in 18 patients via an inferior subxiphoid percutaneous approach (16 with previously failed ablation procedures and 2 patients with long-standing persistent AF) at 2 centers. Epicardial substrate mapping was compared with endocardial mapping to assess transmural uniformity., Results: Of 18 patients, 4 (22%) demonstrated nontransmural atrial low-voltage regions with relative epicardial sparing in the left atrial posterior wall. Transmural isolation of the posterior wall was achieved after an endocardial "box" lesion set in 6/9 (67%), guided by epicardial voltage data, while epicardial and endocardial dissociation during AF was observed in 1 patient. In 3 patients, epicardial capture along the endocardial pulmonary vein lesion set despite endocardial capture loss and bidirectional block was observed. Two cases of mitral flutter were terminated from the epicardium. A balloon was positioned in the pericardial space in 6 patients for esophageal protection during ablation., Conclusion: A percutaneous epicardial approach for mapping and ablation of the left atrium is feasible in the electrophysiology laboratory during endocardial catheter ablation for AF and may be useful as an adjunctive approach in refractory cases. High-density epicardial mapping can provide direct evidence of nonuniform lesion and substrate transmurality of the human left atrium before and after ablation., (Copyright © 2019 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Autonomic dysregulation in cardiovascular disease plays a major role in the pathogenesis of arrhythmias. Cardiac neural control relies on complex feedback loops consisting of efferent and afferent limbs, which carry sympathetic and parasympathetic signals from the brain to the heart and sensory signals from the heart to the brain. Cardiac disease leads to neural remodeling and sympathovagal imbalances with arrhythmogenic effects. Preclinical studies of modulation at central and peripheral levels of the cardiac autonomic nervous system have yielded promising results, leading to early stage clinical studies of these techniques in atrial fibrillation and refractory ventricular arrhythmias, particularly in patients with inherited primary arrhythmia syndromes and structural heart disease. However, significant knowledge gaps in basic cardiac neurophysiology limit the success of these neuromodulatory therapies. This review discusses the recent advances in neuromodulation for cardiac arrhythmia management, with a clinical scenario-based approach aimed at bringing neurocardiology closer to the realm of the clinical electrophysiologist., (Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Atrial fibrillation (AF) is associated with left ventricular (LV) systolic dysfunction which may improve after AF ablation. We hypothesised that increased ventricular irregularity, as measured by R-R dispersion on the baseline ECG, would predict improvement in the left ventricular ejection fraction (LVEF) after AF ablation., Methods: Patients with LVEF <50% at two US centres (2007-2016), having both a preablation and postablation echocardiogram or cardiac MRI, were included. LVEF improvement was defined as absolute increase in LVEF by >7.5%. Multivariable logistic regression (restricted to echocardiographic/ECG variables) was performed to evaluate predictors of LVEF improvement., Results: Fifty-two patients were included in this study. LVEF improved in 30 patients (58%) and was unchanged/worsened in 22 patients (42%). Those with versus without LVEF improvement had an increased baseline R-R dispersion (645±155 ms vs 537±154 ms, p=0.02, respectively). The average baseline heart rate in all patients was 93 beats per minute. After multivariable logistic regression, increased R-R dispersion (OR 1.59, 95% CI 1.00 to 2.55, p=0.03) predicted LVEF improvement., Conclusions: Increased R-R dispersion on ECG was independently associated with improved systolic function after AF ablation. This broadens the existing knowledge of arrhythmia-induced cardiomyopathy, demonstrating that irregular electrical activation (as measured by increased R-R dispersion on ECG) is associated with a cardiomyopathy capable of improving after AF ablation., Competing Interests: Competing interests: None declared.

Introduction: Frequent premature ventricular complexes (PVCs) can lead to symptoms, such as cardiomyopathy and increased mortality. Beta-blockers are recommended as first-line therapy to reduce PVC burden; however, the response is unpredictable. The objective of this study is to determine whether PVC diurnal-variability patterns are associated with different clinical profiles and predict drug response., Methods: Consecutive patients with frequent PVCs (burden ≥ 1%), referred for Holter monitoring between 2014 and 2016, were included. Follow-up Holters, when available, were assessed after beta-blocker initiation to assess response (≥50% reduction). Patients were divided into three groups on the basis of relationship between hourly PVC count and mean HR during each of the 24 Holter hours: (1) fast-HR-dependent-PVC (F-HR-PVC) for positive correlation (Pearson, P < 0.05), (2) slow-HR-dependent-PVC (S-HR-PVC) for a negative, and (3) independent-HR-PVC (I-HR-PVC) when no correlation was found., Results: Of the 416 patients included, 50.2% had F-HR-PVC, 35.6% I-HR-PVC, and 14.2% S-HR-PVC with distinct clinical profiles. Beta-blocker therapy was successful in 34.0% patients overall: patients with F-HR-PVC had a decrease in PVC burden (18.8 ± 10.4% to 9.3 ± 6.6%, P < 0.0001; 62% success), I-HR-PVC had no change (18.4 ± 17.9% to 20.6 ± 17.9%, P = 0.175; 0% success), whereas S-HR-PVC had an increase in burden (14.6 ± 15.3% to 20.8 ± 13.8%, P = 0.016; 0% success). The correlation coefficient was the only predictor of beta-blocker success (AUC = 0.84, sensitivity = 100%, specificity = 67.7%; r ≥ 0.4)., Conclusions: A simple analysis of Holter PVC diurnal variability may provide incremental value to guide clinical PVC management. Only patients displaying a F-HR-PVC profile benefited from beta-blockers. An alternative strategy should be considered for others, as beta-blockers may have no effect or can even be harmful., (© 2019 Wiley Periodicals, Inc.)