Improvement in cardiac function and regional LV strain following intramyocardial injection of a theranostic hydrogel early postmyocardial infarction in a porcine model.

Myocardial infarction (MI) is often complicated by left ventricular (LV) remodeling and heart failure. We evaluated the feasibility of a multimodality imaging approach to guide delivery of an imageable hydrogel and assessed LV functional changes with therapy. Yorkshire pigs underwent surgical occlusions of branches of the left anterior descending and/or circumflex artery to create an anterolateral MI. We evaluated the hemodynamic and mechanical effects of intramyocardial delivery of an imageable hydrogel in the central infarct area (Hydrogel group, n = 8) and a Control group (n = 5) early post-MI. LV and aortic pressure and ECG were measured and contrast cineCT angiography was performed at baseline, 60 min post-MI, and 90 min post-hydrogel delivery. LV hemodynamic indices, pressure-volume measures, and normalized regional and global strains were measured and compared. Both Control and Hydrogel groups demonstrated a decline in heart rate, LV pressure, stroke volume, ejection fraction, and pressure-volume loop area, and an increase in myocardial performance (Tei) index and supply/demand (S/D) ratio. After hydrogel delivery, Tei index and S/D ratio were reduced to baseline levels, diastolic and systolic functional indices either stabilized or improved, and radial strain and circumferential strain increased significantly in the MI regions (ENrr: +52.7%, ENcc: +44.1%). However, the Control group demonstrated a progressive decline in all functional indices to levels significantly below those of Hydrogel group. Thus, acute intramyocardial delivery of a novel imageable hydrogel to MI region resulted in rapid stabilization or improvement in LV hemodynamics and function.NEW & NOTEWORTHY Our study demonstrates that contrast cineCT imaging can be used to evaluate the acute effects of intramyocardial delivery of a therapeutic hydrogel to the central MI region early post MI, which resulted in a rapid stabilization of LV hemodynamics and improvement in regional and global LV function.

Quantification of intramyocardial blood volume using 99mTc-RBC SPECT/CT: a pilot human study.

BACKGROUND: Quantification of intramyocardial blood volume (IMBV), the fraction of myocardium that is occupied by blood, is a promising Index to measure microcirculatory functions. In previous large animal SPECT/CT studies injected with 99mTc-labeled Red Blood Cell (RBC) and validated by ex vivo microCT, we have demonstrated that accurate IMBV can be measured. In this study, we report the data processing methods and results of the first-in-human pilot study. METHODS: Data from three subjects have been included to date. Each subject underwent rest and adenosine-induced stress 99mTc-RBC SPECT/CT on a dedicated cardiac system with both non-contrast and contrast-enhanced CT acquired. Corrections of attenuation (AC) and scatter (SC), respiratory and cardiac gating, and partial volume correction (PVC) were applied. We also performed automatic segmentation and registration approach based on the blood pool topology in both SPECT and CT images. RESULTS: The quantified IMBV across all subjects under resting conditions were 35.0% ± 3.3% for the end-diastolic phase and 24.1% ± 2.7% for the end-systolic phase. The cycle-dependent change in IMBV (ΔIMBV) between diastolic and systolic phases was 31.5% ± 3.0%. Under stress, IMBV were 40.6% ± 4.2% for the end-diastolic phase and 26.5% ± 2.8% for the end-systolic phase, and ΔIMBV was 34.7% ± 7.4%. CONCLUSIONS: It is feasible to quantify IMBV in resting and stress conditions in human studies using SPECT/CT with 99mTc-RBC.

Anger recall mental stress decreases 123I-metaiodobenzylguanidine (123I-MIBG) uptake and increases heterogeneity of cardiac sympathetic activity in the myocardium in patients with ischemic cardiomyopathy.

BACKGROUND: Acute psychological stressors such as anger can precipitate ventricular arrhythmias, but the mechanism is incompletely understood. Quantification of regional myocardial sympathetic activity with 123I-metaiodobenzylguanidine (123I-mIBG) SPECT imaging in conjunction with perfusion imaging during mental stress may identify a mismatch between perfusion and sympathetic activity that may exacerbate a mismatch between perfusion and sympathetic activity that could create a milieu of increased vulnerability to ventricular arrhythmia. METHODS: Five men with ischemic cardiomyopathy (ICM), and five age-matched healthy male controls underwent serial 123I-mIBG and 99mTc-Tetrofosmin SPECT/CT imaging during an anger recall mental stress task and dual isotope imaging was repeated approximately 1 week later during rest. Images were reconstructed using an iterative reconstruction algorithm with CT-based attenuation correction. The mismatch of left ventricular myocardial 123I-mIBG and 99mTc-Tetrofosmin was assessed along with radiotracer heterogeneity and the 123I-mIBG heart-to-mediastinal ratios (HMR) were calculated using custom software developed at Yale. RESULTS: The hemodynamic response to mental stress was similar in both groups. The resting-HMR was greater in healthy control subjects (3.67 ± 0.95) than those with ICM (3.18 ± 0.68, P = .04). Anger recall significantly decreased the HMR in ICM patients (2.62 ± 0.3, P = .04), but not in normal subjects. The heterogeneity of 123I-mIBG uptake in the myocardium was significantly increased in ICM patients during mental stress (26% ± 8.23% vs. rest: 19.62% ± 9.56%; P = .01), whereas the 99mTc-Tetrofosmin uptake pattern was unchanged. CONCLUSION: Mental stress decreased the 123I-mIBG HMR, increased mismatch between sympathetic activity and myocardial perfusion, and increased the heterogeneity of 123I-mIBG uptake in ICM patients, while there was no significant change in myocardial defect size or the heterogeneity of 99mTc-Tetrofosmin perfusion. The changes observed in this proof-of-concept study may provide valuable information about the trigger-substrate interaction and the potential vulnerability for ventricular arrhythmias.

Astrocytes and retrograde degeneration of nigrostriatal dopaminergic neurons in Parkinson's disease: removing axonal debris.

OBJECTIVE: The dopaminergic nigrostriatal neurons (DA cells) in healthy people present a slow degeneration with aging, which produces cellular debris throughout life. About 2%-5% of people present rapid cell degeneration of more than 50% of DA cells, which produces Parkinson's disease (PD). Neuroinflammation accelerates the cell degeneration and may be critical for the transition between the slow physiological and the rapid pathological degeneration of DA cells, particularly when it activates microglial cells of the medial forebrain bundle near dopaminergic axons. As synaptic debris produced by DA cell degeneration may trigger the parkinsonian neuroinflammation, this study investigated the removal of axonal debris produced by retrograde degeneration of DA cells, paying particular attention to the relative roles of astrocytes and microglia. METHODS: Rats and mice were injected in the lateral ventricles with 6-hydroxydopamine, inducing a degeneration of dopaminergic synapses in the striatum which was not accompanied by non-selective tissue damage, microgliosis or neuroinflammation. The possible retrograde degeneration of dopaminergic axons, and the production and metabolization of DA-cell debris were studied with immunohistochemical methods and analyzed in confocal and electron microscopy images. RESULTS: The selective degeneration of dopaminergic synapses in the striatum was followed by a retrograde degeneration of dopaminergic axons whose debris was found within spheroids of the medial forebrain bundle. These spheroids retained mitochondria and most (e.g., tyrosine hydroxylase, the dopamine transporter protein, and amyloid precursor protein) but not all (e.g., α-synuclein) proteins of the degenerating dopaminergic axons. Spheroids showed initial (autophagosomes) but not late (lysosomes) components of autophagy (incomplete autophagy). These spheroids were penetrated by astrocytic processes of the medial forebrain bundle, which provided the lysosomes needed to continue the degradation of dopaminergic debris. Finally, dopaminergic proteins were observed in the cell somata of astrocytes. No microgliosis or microglial phagocytosis of debris was observed in the medial forebrain bundle during the retrograde degeneration of dopaminergic axons. CONCLUSIONS: The present data suggest a physiological role of astrocytic phagocytosis of axonal debris for the medial forebrain bundle astrocytes, which may prevent the activation of microglia and the spread of retrograde axonal degeneration in PD.

Effect of Hydroxychloroquine on QTc in Patients Diagnosed with COVID-19: A Systematic Review and Meta-Analysis.

BACKGROUND: Hydroxychloroquine or chloroquine with or without the concomitant use of azithromycin have been widely used to treat patients with SARS-CoV-2 infection, based on early in vitro studies, despite their potential to prolong the QTc interval of patients. OBJECTIVE: This is a systematic review and metanalysis designed to assess the effect of hydroxychloroquine with or without the addition of azithromycin on the QTc of hospitalized patients with COVID-19. MATERIALS AND METHODS: PubMed, Scopus, Cochrane and MedRxiv databases were reviewed. A random effect model meta-analysis was used, and I-square was used to assess the heterogeneity. The prespecified endpoints were ΔQTc, QTc prolongation > 500 ms and ΔQTc > 60 ms. RESULTS: A total of 18 studies and 7179 patients met the inclusion criteria and were included in this systematic review and meta-analysis. The use of hydroxychloroquine with or without the addition of azithromycin was associated with increased QTc when used as part of the management of patients with SARS-CoV-2 infection. The combination therapy with hydroxychloroquine plus azithromycin was also associated with statistically significant increases in QTc. Moreover, the use of hydroxychloroquine alone, azithromycin alone, or the combination of the two was associated with increased numbers of patients that developed QTc prolongation > 500 ms. CONCLUSION: This systematic review and metanalysis revealed that the use of hydroxychloroquine alone or in conjunction with azithromycin was linked to an increase in the QTc interval of hospitalized patients with SARS-CoV-2 infection that received these agents.

The dynamic of basal ganglia activity with a multiple covariance method: influences of Parkinson's disease.

The closed-loop cortico-subcortical pathways of basal ganglia have been extensively used to describe the physiology of these centres and to justify the functional disorders of basal ganglia diseases. This approach justifies some experimental and clinical data but not others, and furthermore, it does not include a number of subcortical circuits that may produce a more complex basal ganglia dynamic than that expected for closed-loop linear networks. This work studied the functional connectivity of the main regions of the basal ganglia motor circuit with magnetic resonance imaging and a new method (functional profile method), which can analyse the multiple covariant activity of human basal ganglia. The functional profile method identified the most frequent covariant functional status (profiles) of the basal ganglia motor circuit, ordering them according to their relative frequency and identifying the most frequent successions between profiles (profile transitions). The functional profile method classified profiles as input profiles that accept the information coming from other networks, output profiles involved in the output of processed information to other networks and highly interconnected internal profiles that accept transitions from input profiles and send transitions to output profiles. Profile transitions showed a previously unobserved functional dynamic of human basal ganglia, suggesting that the basal ganglia motor circuit may work as a dynamic multiple covariance network. The number of internal profiles and internal transitions showed a striking decrease in patients with Parkinson's disease, a fact not observed for input and output profiles. This suggests that basal ganglia of patients with Parkinson's disease respond to requirements coming from other neuronal networks, but because the internal processing of information is drastically weakened, its response will be insufficient and perhaps also self-defeating. These marked effects were found in patients with few motor disorders, suggesting that the functional profile method may be an early procedure to detect the first stages of the Parkinson's disease when the motor disorders are not very evident. The multiple covariance activity found presents a complementary point of view to the cortico-subcortical closed-loop model of basal ganglia. The functional profile method may be easily applied to other brain networks, and it may provide additional explanations for the clinical manifestations of other basal ganglia disorders.

Neuroglial transmitophagy and Parkinson's disease.

Mitophagy is essential for the health of dopaminergic neurons because mitochondrial damage is a keystone of Parkinson's disease. The aim of the present work was to study the degradation of mitochondria in the degenerating dopaminergic synapse. Adult Sprague-Dawley rats and YFP-Mito-DAn mice with fluorescent mitochondria in dopaminergic neurons were injected in the lateral ventricles with 6-hydroxydopamine, a toxic that inhibits the mitochondrial chain of dopaminergic neurons and blockades the axonal transport. Dopaminergic terminals closest to the lateral ventricle showed an axonal fragmentation and an accumulation of damaged mitochondria in 2-9 µ saccular structures (spheroids). Damaged mitochondria accumulated in spheroids initiated (showing high Pink1, parkin, ubiquitin, p-S65-Ubi, AMBRA1, and BCL2L13 immunoreactivity and developing autophagosomes) but did not complete (mitochondria were not polyubiquitinated, autophagosomes had no STX17, and no lysosomes were found in spheroids) the mitophagy process. Then, spheroids were penetrated by astrocytic processes and DAergic mitochondria were transferred to astrocytes where they were polyubiquitinated (UbiK63+) and linked to mature autophagosomes (STX17+) which became autophagolysosomes (Lamp1/Lamp2 which co-localized with LC3). Present data provide evidence that the mitophagy of degenerating dopaminergic terminals starts in the dopaminergic spheroids and finishes in the surrounding astrocytes (spheroid-mediated transmitophagy). The neuron-astrocyte transmitophagy could be critical for preventing the release of damaged mitochondria to the extracellular medium and the neuro-inflammatory activity which characterizes Parkinson's disease.

Differential Aggregation and Phosphorylation of Alpha Synuclein in Membrane Compartments Associated With Parkinson Disease.

The aggregation of α-synuclein (α-syn) is a major factor behind the onset of Parkinson's disease (PD). Sublocalization of this protein may be relevant for the formation of multimeric α-syn oligomeric configurations, insoluble aggregates that form Lewy bodies in PD brains. Processing of this protein aggregation is regulated by associations with distinct lipid classes. For instance, instability of lipid raft (LR) microdomains, membrane regions with a particular lipid composition, is an early event in the development of PD. However, the relevance of membrane microdomains in the regulation and trafficking of the distinct α-syn configurations associated with PD remains unexplored. In this study, using 6- and 14-month-old healthy and MPTP-treated animals as a model of PD, we have investigated the putative molecular alterations of raft membrane microstructures, and their impact on α-syn dynamics and conformation. A comparison of lipid analyses of LR microstructures and non-raft (NR) fractions showed alterations in gangliosides, cholesterol, polyunsaturated fatty acids (PUFA) and phospholipids in the midbrain and cortex of aged and MPTP-treated mice. In particular, the increase of PUFA and phosphatidylserine (PS) during aging correlated with α-syn multimeric formation in NR. In these aggregates, α-syn was phosphorylated in pSer129, the most abundant post-transductional modification of α-syn promoting toxic aggregation. Interestingly, similar variations in PUFA and PS content correlating with α-syn insoluble accumulation were also detected in membrane microstructures from the human cortex of incidental Parkinson Disease (iPD) and PD, as compared to healthy controls. Furthermore, structural changes in membrane lipid microenvironments may induce rearrangements in raft-interacting proteins involved in other neuropathologies. Therefore, we also investigated the dynamic of other protein markers involved in cognition and memory impairment such as metabotropic glutamate receptor 5 (mGluR5), ionotropic NMDA receptor (NMDAR2B), prion protein (PrPc) and amyloid precursor protein (APP), whose activity depends on membrane lipid organization. We observed a decline of these protein markers in LR fractions with the progression of aging and pathology. Overall, our findings demonstrate that lipid alterations in membranous compartments promoted by brain aging and PD-like injury may have an effect on α-syn aggregation and segregation in abnormal multimeric structures.

Mastering the art of epicardial access in cardiac electrophysiology.

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 CO2 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.

Brugada Syndrome: Progress in Genetics, Risk Stratification and Management.

Brugada syndrome (BrS) is one of the most common causes of sudden cardiac death in normal structural heart individuals. First characterised in 1992, the global prevalence of BrS is unclear, with estimates placing it at around 0.05% and presenting most frequently in southeast Asian countries. This review aims to summarise the development in the understanding of BrS and, importantly, progress in its management, underpinned by knowledge regarding its genetics and molecular mechanisms. It also provides update on risk stratification and promising new therapies for BrS, including epicardial ablation. Future studies are required to increase understanding of the pathogenesis of this disease and to guide clinical practice.

Combined Endocardial-Epicardial Versus Endocardial Catheter Ablation Alone for Ventricular Tachycardia in Structural Heart Disease: A Systematic Review and Meta-Analysis.

OBJECTIVES: This study sought to determine whether combined endocardial-epicardial (endo-epi) ablation was superior to endocardial only ablation in patients with scar-related ventricular tachycardia (VT). BACKGROUND: Limited single-center studies suggest that combined endo-epi ablation strategy may be superior to endocardial ablation (endo) alone in patients with nonischemic cardiomyopathy (NICM) and arrhythmogenic right ventricular cardiomyopathy (ARVC), and ischemic cardiomyopathy (ICM). METHODS: A systematic review of Medline, Cochrane, and Embase databases was performed for studies that reported outcomes comparing endo-epi with endo VT ablation alone. RESULTS: Seventeen studies consisting of 975 patients were included (mean 56 ± 10 years of age; 79% male; NICM in 36.6%; ICM in 32.8%; and ARVC in 30.6%). After a mean follow-up of 27 ± 21 months, endo-epi ablation was associated with a 35% reduction in risk of VT recurrence compared with endocardial ablation alone (risk ratio [RR]: 0.65; 95% confidence interval [CI]: 0.55 to 0.78; p < 0.001). Sensitivity analysis showed lower risk of VT recurrence in ICM (RR: 0.43; 95% CI: 0.28 to 0.67; p = 0.0002) and ARVC (RR: 0.59; 95% CI: 0.43 to 0.82; p = 0.0002), with a nonsignificant trend in NICM (RR: 0.87; 95% CI: 0.70 to 1.08; p = 0.20). Endo-epi, compared with endo ablation, was associated with reduced all-cause mortality (RR: 0.56; 95% CI: 0.32 to 0.97; p = 0.04). Acute procedural complications were higher with the endo-epi approach (RR: 2.62; 95% CI: 0.91 to 7.52; p = 0.07). CONCLUSIONS: This meta-analysis suggests that a combined endo-epi ablation is associated with a lower risk of VT recurrence and subsequent mortality than endo only VT ablation in patients with scar-related VT. Procedural complications, however, are higher with the endo-epi approach.

Clinical outcomes in patients with atrial fibrillation receiving amiodarone on NOACs vs. warfarin.

PURPOSE: Amiodarone is a potent inhibitor of the CYP450:3A4 and inhibitor of the P-glycoprotein, both of which metabolize new oral anticoagulants (NOACs). Patients who are on NOACs and are concomitantly treated with amiodarone may have a higher risk of major bleeding according to recent retrospective trials. Whether this increased risk outweighs the benefits of NOACs compared to warfarin is unknown. We aimed to compare clinical outcomes between NOACs and warfarin in patients with atrial fibrillation (AF) being treated with amiodarone. METHODS: We performed a systematic review of MEDLINE, Cochrane, and Embase for randomized controlled trials that compared NOACs to warfarin for prophylaxis of ischemic stroke/thromboembolic events (TEs) in patients with AF and reported outcomes on TE, major bleeding, and intracranial bleeding (ICB). Risk ratio (RR) and 95% confidence intervals were measured using the Mantel-Haenszel method. Fixed effects model was used, and if heterogeneity (I2) was > 25%, effects were analyzed using a random model. RESULTS: A total of four studies comparing NOACs to warfarin were included in the analysis. The total number of patients on amiodarone was 6197. Mean follow up was 23 ± 5 months. No statistically significant difference for TE prevention (RR, 0.73; 95% CI 0.50-1.07), major bleeding (RR, 1.02; 95% CI 0.68-1.53), or ICB outcomes (RR, 0.58; 95% CI 0.22-1.51) between patients on NOACs + amiodarone when compared to patients on warfarin + amiodarone. CONCLUSION: Among patients with AF taking amiodarone, there is no increased risk of stroke, major bleeding, or ICB with NOACs compared to warfarin.

Is it safe to stop oral anticoagulation after catheter ablation for atrial fibrillation?

INTRODUCTION: Atrial fibrillation is the most common arrhythmia worldwide. Its increasing prevalence has made the use of oral anticoagulants for stroke prevention routine; however, their use after the blanking period of catheter ablation remains uncertain. Areas covered: This review outlines the pros and cons of stopping oral anticoagulation after catheter ablation. Major databases such as Pubmed or Embase were used. The most relevant articles published were used along with major recommendations of society guidelines. Authors will also discuss different proposed mechanisms of atrial fibrillation and more importantly future directions in this topic. Expert commentary: The use of oral anticoagulants after catheter ablation for atrial fibrillation is debatable; however, based on current guidelines, we support the use of oral anticoagulants after the blanking period of catheter ablation. Noteworthy is that although the risk of bleeding can be fatal in some cases, it does not outweigh the risk of a disabling stroke.

Bivalirudin versus heparin in patients undergoing percutaneous peripheral interventions: A systematic review and meta-analysis.

BACKGROUND: Bivalirudin may be an effective alternative anticoagulant to heparin for use in percutaneous peripheral interventions. We aimed to compare the safety and efficacy of bivalirudin versus heparin as the procedural anticoagulant agent in patients undergoing percutaneous peripheral intervention. METHODS: For this meta-analysis and systematic review, we conducted a search in PubMed, Medline, Embase, and Cochrane for all the clinical studies in which bivalirudin was compared to heparin as the procedural anticoagulant in percutaneous peripheral interventions. Outcomes studied included all-cause mortality, all-bleeding, major and minor bleeding, and access site complications. RESULTS: Eleven studies were included in the analysis, totaling 20,137 patients. There was a significant difference favoring bivalirudin over heparin for all-cause mortality (risk ratio 0.58, 95% CI 0.39-0.87), all-bleeding (risk ratio 0.62, 95% CI 0.50-0.78), major bleeding (risk ratio 0.61, 95% CI 0.39-0.96), minor bleeding (risk ratio 0.66, 95% CI 0.47-0.92), and access site complications (risk ratio 0.66, 95% CI 0.51-0.84). There was no significant difference in peri-procedural need for blood transfusions (risk ratio 0.79, 95% CI 0.57-1.08), myocardial infarction (risk ratio 0.87, 95% CI 0.59-1.28), stroke (risk ratio 0.77, 95% CI 0.59-1.01), intracranial bleeding (risk ratio 0.77, 95% CI 0.29-2.02), or amputations (OR 0.75, 95% CI 0.53-1.05). CONCLUSION: Our meta-analysis suggests that bivalirudin use for percutaneous peripheral interventions is associated with lower all-cause mortality, bleeding, and access site complications as compared to heparin. Further large randomized trials are needed to confirm the current results.

Early Versus Late Referral for Catheter Ablation of Ventricular Tachycardia in Patients With Structural Heart Disease: A Systematic Review and Meta-Analysis of Clinical Outcomes.

OBJECTIVES: This was a meta-analysis of published studies to examine the impact of early referral on outcomes after catheter ablation for ventricular tachycardia (VT) in patients with structural heart disease. BACKGROUND: Patients are frequently referred for VT ablation after failure of antiarrhythmic drugs to control VT. Some studies have suggested that early referral might confer better outcomes. METHODS: An electronic search was performed using major databases. The primary outcomes were long-term VT recurrence and total mortality. Secondary outcomes were acute procedural success and acute complications. RESULTS: Three studies were included with a total of 980 patients (mean age 64 ± 12 years, 71% males). Mean follow-up was 29 ± 27 months. Early referral for VT ablation was associated with decreased VT recurrence and acute complications compared with late referral (relative risk: 0.69 [95% confidence interval: 0.58 to 0.82], p < 0.0001 and relative risk: 0.50 [95% confidence interval: 0.27 to 0.93], p = 0.03, respectively). There was no significant difference between early and late referral for total mortality and acute success. CONCLUSIONS: Late referral for VT ablation was associated with worse outcomes (VT recurrence and acute complications) in patients with structural heart disease, which suggests that early referral for VT ablation might be a reasonable consideration in this patient population.

Uninterrupted direct oral anticoagulants vs. uninterrupted vitamin K antagonists during catheter ablation of non-valvular atrial fibrillation: a systematic review and meta-analysis of randomized controlled trials.

Aims: To assess the incremental benefit of uninterrupted direct oral anticoagulants (DOACs) vs. uninterrupted vitamin K antagonists (VKA) for catheter ablation (CA) of non-valvular atrial fibrillation (NVAF) on three primary outcomes: major bleeding, thrombo-embolic events, and minor bleeding. A secondary outcome was post-procedural silent cerebral infarction (SCI) as detected by brain magnetic resonance imaging. Methods and results: A systematic review of Medline, Cochrane, and Embase was done to find all randomized controlled trials (RCTs) in which uninterrupted DOACs were compared against uninterrupted VKA for CA of NVAF. A fixed-effect model was used, with the exception of the analysis regarding major bleeding events (I2 > 25), for which a random effects model was used. The benefit of uninterrupted DOACs over VKA was analysed from four RCTs that enrolled a total of 1716 patients (male: 71.2%) with NVAF. Of these, 1100 patients (64.1%) had paroxysmal atrial fibrillation. No significant benefit was seen in major bleeding events [risk ratio (RR) 0.54, 95% confidence interval (95% CI) 0.29-1.00; P = 0.05]. No significant differences were found in minor bleeding events (RR 1.11, 95% CI 0.82-1.52; P = 0.50), thrombo-embolic events (RR 0.74, 95% CI 0.26-2.11; P = 0.57), or post-procedural SCI (RR 1.06, 95% CI 0.74-1.53; P = 0.74). Conclusion: An uninterrupted DOACs strategy for CA of NVAF appears to be as safe as uninterrupted VKA without a significantly increased risk of minor or major bleeding events. There was a trend favouring DOACs in terms of major bleeding. Given their ease of use, fewer drug interactions and a similar security and effectiveness profile, DOACs should be considered first line therapy in patients undergoing CA for NVAF.

Oesophageal Injury During AF Ablation: Techniques for Prevention.

Atrial fibrillation remains the most common arrhythmia worldwide, with pulmonary vein isolation (PVI) being an essential component in the treatment of this arrhythmia. In view of the close proximity of the oesophagus with the posterior wall of the left atrium, oesophageal injury prevention has become a major concern during PVI procedures. Oesophageal changes varying from erythema to fistulas have been reported, with atrio-oesophageal fistulas being the most feared as they are associated with major morbidity and mortality. This review article provides a detailed description of the risk factors associated with oesophageal injury during ablation, along with an overview of the currently available techniques to prevent oesophageal injury. We expect that this state of the art review will deliver the tools to help electrophysiologists prevent potential oesophageal injuries, as well as increase the focus on research areas in which evidence is lacking.

Benefit of left atrial appendage electrical isolation for persistent and long-standing persistent atrial fibrillation: a systematic review and meta-analysis.

Aims: The long-term outcomes of left atrial appendage electrical isolation (LAAEI) in patients with non-paroxysmal atrial fibrillation (AF) have corroborated the significant role of the LAA in this arrhythmia. We sought to investigate the incremental benefit of LAAEI in patients undergoing catheter ablation for persistent AF or long-standing persistent AF (LSPAF). Methods and results: A systematic review of Medline, Cochrane, and Embase for all the clinical studies in which assessment LAAEI in non-paroxysmal AF patients was performed. The benefit of LAAEI in patients with AF was analysed from seven studies that enrolled a total of 930 patients [mean age 63 ± 5 years; male: 69%]. All studies included patients with either persistent AF or LSPAF or the combination of them. The overall freedom from all-arrhythmia recurrence at 12 months of follow-up off antiarrhythmic medications in patients who underwent LAAEI was 75.5% vs. 43.9% in those in whom only standard ablation was performed [56% relative reduction and 31.6% absolute reduction; risk ratio (RR) 0.44, 95% confidence interval (95% CI) 0.31-0.64; P < 0.0001]. The rate of ischaemic stroke in the LAAEI group was 0.4% and in the control group 2.1% at 12 months follow-up (RR 0.40, 95% CI 0.12-1.30; P = 0.13). Acute complications rates were identical between groups [LAAEI 5.5%, control 5.5% (RR 0.99, 95% CI 0.46-2.16; P = 0.99)]. Conclusion: Left atrial appendage electrical isolation in addition to standard ablation appears to have a substantial incremental benefit to achieve freedom from ALL atrial arrhythmias in patients with persistent AF and LSPAF without increasing acute procedural complications and without raising the risk of ischaemic stroke.

Clinical impact of implantable cardioverter-defibrillator in primary prevention of total mortality in non-ischaemic cardiomyopathy: results from a meta-analysis of prospective randomized clinical trials.

Aim: Primary prophylactic implantable cardioverter defibrillators (ICDs) have demonstrated a clear all-cause mortality benefit in patients with ischaemic cardiomyopathy, with less compelling evidence supporting its use in patients with non-ischaemic cardiomyopathy (NICM). We performed a meta-analysis of randomized controlled trials (RCTs) evaluating the role of ICD for reduction in total mortality in NICM patients. Methods and results: An electronic search on PubMed, the Cochrane Library, and EMBASE databases was performed to identify the RCTs evaluating the role of prophylactic ICD placement in NICM patients. Mantel-Haenszel risk ratio (RR) fixed-effects model was used to summarize data across treatment arms. Random-effects model was used if heterogeneity (I2) ≥ 25. Patients with cardiac resynchronization therapy pacemaker (CRT-P) were included in the control group. Six RCTs, with a total of 3128 patients and a mean follow-up period of 48 ± 22 months comparing ICD with medical therapy in NICM were included in this analysis. There was a significant reduction in all-cause mortality in the ICD group compared with the medical therapy group [RR 0.79, 95% confidence interval (95% CI) 0.68-0.92; P = 0.002]. No publication bias was noted. Conclusion: Currently available evidence demonstrates that the use of ICD provides a clear and significant reduction in all-cause mortality among patients with NICM.