Structural Basis for Blocking Sugar Uptake into the Malaria Parasite Plasmodium falciparum.

Plasmodium species, the causative agent of malaria, rely on glucose for energy supply during blood stage. Inhibition of glucose uptake thus represents a potential strategy for the development of antimalarial drugs. Here, we present the crystal structures of PfHT1, the sole hexose transporter in the genome of Plasmodium species, at resolutions of 2.6 Å in complex with D-glucose and 3.7 Å with a moderately selective inhibitor, C3361. Although both structures exhibit occluded conformations, binding of C3361 induces marked rearrangements that result in an additional pocket. This inhibitor-binding-induced pocket presents an opportunity for the rational design of PfHT1-specific inhibitors. Among our designed C3361 derivatives, several exhibited improved inhibition of PfHT1 and cellular potency against P. falciparum, with excellent selectivity to human GLUT1. These findings serve as a proof of concept for the development of the next-generation antimalarial chemotherapeutics by simultaneously targeting the orthosteric and allosteric sites of PfHT1.

Orthosteric-allosteric dual inhibitors of PfHT1 as selective antimalarial agents.

Artemisinin-resistant malaria parasites have emerged and have been spreading, posing a significant public health challenge. Antimalarial drugs with novel mechanisms of action are therefore urgently needed. In this report, we exploit a "selective starvation" strategy by inhibiting Plasmodium falciparum hexose transporter 1 (PfHT1), the sole hexose transporter in P. falciparum, over human glucose transporter 1 (hGLUT1), providing an alternative approach to fight against multidrug-resistant malaria parasites. The crystal structure of hGLUT3, which shares 80% sequence similarity with hGLUT1, was resolved in complex with C3361, a moderate PfHT1-specific inhibitor, at 2.3-Å resolution. Structural comparison between the present hGLUT3-C3361 and our previously reported PfHT1-C3361 confirmed the unique inhibitor binding-induced pocket in PfHT1. We then designed small molecules to simultaneously block the orthosteric and allosteric pockets of PfHT1. Through extensive structure-activity relationship studies, the TH-PF series was identified to selectively inhibit PfHT1 over hGLUT1 and potent against multiple strains of the blood-stage P. falciparum Our findings shed light on the next-generation chemotherapeutics with a paradigm-shifting structure-based design strategy to simultaneously target the orthosteric and allosteric sites of a transporter.

Peri-procedural anticoagulation in patients with end-stage kidney disease undergoing atrial fibrillation ablation: results from the multicentre end-stage kidney disease-atrial fibrillation ablation registry.

AIMS: The optimal anticoagulation regimen in patients with end-stage kidney disease (ESKD) undergoing atrial fibrillation (AF) catheter ablation is unknown. We sought to describe the real-world practice of peri-procedural anticoagulation management in patients with ESKD undergoing AF ablation. METHODS AND RESULTS: Patients with ESKD on haemodialysis undergoing catheter ablation for AF in 12 referral centres in Japan were included. The international normalized ratio (INR) before and 1 and 3 months after ablation was collected. Peri-procedural major haemorrhagic events as defined by the International Society on Thrombosis and Haemostasis, as well as thromboembolic events, were adjudicated. A total of 347 procedures in 307 patients (67 ±9 years, 40% female) were included. Overall, INR values were grossly subtherapeutic [1.58 (interquartile range: 1.20-2.00) before ablation, 1.54 (1.22-2.02) at 1 month, and 1.22 (1.01-1.71) at 3 months]. Thirty-five patients (10%) suffered major complications, the majority of which was major bleeding (19 patients; 5.4%), including 11 cardiac tamponade (3.2%). There were two peri-procedural deaths (0.6%), both related to bleeding events. A pre-procedural INR value of 2.0 or higher was the only independent predictor of major bleeding [odds ratio, 3.3 (1.2-8.7), P = 0.018]. No cerebral or systemic thromboembolism occurred. CONCLUSION: Despite most patients with ESKD undergoing AF ablation showing undertreatment with warfarin, major bleeding events are common while thromboembolic events are rare.

Diversity-oriented synthesis yields novel multistage antimalarial inhibitors.

Antimalarial drugs have thus far been chiefly derived from two sources-natural products and synthetic drug-like compounds. Here we investigate whether antimalarial agents with novel mechanisms of action could be discovered using a diverse collection of synthetic compounds that have three-dimensional features reminiscent of natural products and are underrepresented in typical screening collections. We report the identification of such compounds with both previously reported and undescribed mechanisms of action, including a series of bicyclic azetidines that inhibit a new antimalarial target, phenylalanyl-tRNA synthetase. These molecules are curative in mice at a single, low dose and show activity against all parasite life stages in multiple in vivo efficacy models. Our findings identify bicyclic azetidines with the potential to both cure and prevent transmission of the disease as well as protect at-risk populations with a single oral dose, highlighting the strength of diversity-oriented synthesis in revealing promising therapeutic targets.

Modular, stereocontrolled Cß-H/Cα-C activation of alkyl carboxylic acids.

The union of two powerful transformations, directed C-H activation and decarboxylative cross-coupling, for the enantioselective synthesis of vicinally functionalized alkyl, carbocyclic, and heterocyclic compounds is described. Starting from simple carboxylic acid building blocks, this modular sequence exploits the residual directing group to access more than 50 scaffolds that would be otherwise extremely difficult to prepare. The tactical use of these two transformations accomplishes a formal vicinal difunctionalization of carbon centers in a way that is modular and thus, amenable to rapid diversity incorporation. A simplification of routes to known preclinical drug candidates is presented along with the rapid diversification of an antimalarial compound series.

Plasmodium parasite exploits host aquaporin-3 during liver stage malaria infection.

Within the liver a single Plasmodium parasite transforms into thousands of blood-infective forms to cause malaria. Here, we use RNA-sequencing to identify host genes that are upregulated upon Plasmodium berghei infection of hepatocytes with the hypothesis that host pathways are hijacked to benefit parasite development. We found that expression of aquaporin-3 (AQP3), a water and glycerol channel, is significantly induced in Plasmodium-infected hepatocytes compared to uninfected cells. This aquaglyceroporin localizes to the parasitophorous vacuole membrane, the compartmental interface between the host and pathogen, with a temporal pattern that correlates with the parasite's expansion in the liver. Depletion or elimination of host AQP3 expression significantly reduces P. berghei parasite burden during the liver stage and chemical disruption by a known AQP3 inhibitor, auphen, reduces P. falciparum asexual blood stage and P. berghei liver stage parasite load. Further use of this inhibitor as a chemical probe suggests that AQP3-mediated nutrient transport is an important function for parasite development. This study reveals a previously unknown potential route for host-dependent nutrient acquisition by Plasmodium which was discovered by mapping the transcriptional changes that occur in hepatocytes throughout P. berghei infection. The dataset reported may be leveraged to identify additional host factors that are essential for Plasmodium liver stage infection and highlights Plasmodium's dependence on host factors within hepatocytes.

Characteristics of the nonpulmonary vein foci induced after second-generation cryoballoon ablation for paroxysmal atrial fibrillation.

INTRODUCTION: Pulmonary vein isolation (PVI) using cryoballoon is effective for patients with paroxysmal atrial fibrillation (PAF); however, few reports have evaluated the non-pulmonary vein (PV) foci after cryoballoon ablation. We aimed to evaluate the characteristics of non-PV foci and predictors of atrial fibrillation (AF) recurrence after cryoballoon ablation. METHODS AND RESULTS: This was a single-center retrospective study of 647 patients with PAF who underwent initial PVI using a second-generation cryoballoon. After PVI, all patients underwent high-dose isoproterenol infusion to assess the existence of non-PV foci. Non-PV foci were observed in 211 patients (32.6%), which were most frequently observed in the superior vena cava. Higher age (odds ratio [OR] = 1.02; 95% confidence interval [CI] = 1.00-1.04; P = .025), female sex (OR = 1.65; 95% CI = 1.13-2.41; P = .009), and lower body mass index (OR = 0.95; 95% CI = 0.89-1.00; P = .049) were significantly associated with non-PV foci. The existence of non-PV foci was an independent predictor of AF recurrence (Hazard's ratio = 1.70; 95% CI = 1.12-2.60; P = .014). When non-PV foci were mappable and successfully ablated, patients with non-PV foci showed similar outcomes with those without non-PV foci (1-year AF-free survival rates of 88.5% vs 91.5%; P = .338). Conversely, when we failed to detect and eliminate non-PV foci because they had multiple origins and were not consistently inducible (multichanging non-PV foci), the 1-year AF-free survival rate was 56.4% even after substrate modification. CONCLUSION: Non-PV foci were observed in one-third of patients with PAF after cryoballoon ablation and were associated with AF recurrence. Catheter ablation for non-PV foci was effective when they were mappable; however, multichanging non-PV foci were associated with worse prognosis.

Rapid and Systematic Exploration of Chemical Space Relevant to Artemisinins: Anti-malarial Activities of Skeletally Diversified Tetracyclic Peroxides and 6-Aza-artemisinins.

To achieve both structural changes and rapid synthesis of the tetracyclic scaffold relevant to artemisinins, we explored two kinds of de novo synthetic approaches that generate both skeletally diversified tetracyclic peroxides and 6-aza-artemisinins. The anti-malarial activities of the tetracyclic peroxides with distinct skeletal arrays, however, were moderate and far inferior to artemisinins. Given the privileged scaffold of artemisinins, we next envisioned element implantation at the C6 position with a nitrogen without the trimmings of substituents and functional groups. This molecular design allowed the deep-seated structural modification of the hitherto unexplored cyclohexane moiety (C-ring) while keeping the three-dimensional structure of artemisinins. Notably, this approach induced dramatic changes of retrosynthetic transforms that allow an expeditious catalytic asymmetric synthesis with generation of substitutional variations at three sites (N6, C9, and C3) of the 6-aza-artemisinins. These de novo synthetic approaches led to the lead discovery with substantial intensification of the in vivo activities, which undermine the prevailing notion that the C-ring of artemisinins appears to be merely a structural unit but to be a functional area as the anti-malarial pharmacophore. Furthermore, we unexpectedly found that racemic 6-aza-artemisinin (33) exerted exceedingly potent in vivo efficacies superior to the chiral one and the first-line drug, artesunate.

Natural product-inspired aryl isonitriles as a new class of antimalarial compounds against drug-resistant parasites.

Malaria is a prevalent and deadly disease. The fast emergence of drug-resistant malaria parasites makes the situation even worse. Thus, developing new chemical entities, preferably with novel mechanisms of action, is urgent and important. Inspired by the complex and scarce isonitrile-containing terpene natural products, we evaluated a collection of easily prepared synthetic mono- and bis-isonitrile compounds, most of which feature a simple, but rigid stilbene backbone. From this collection, potent antimalarial lead compounds with EC50 value ranging from 27 to 88 nM against the Dd2 strain using a blood stage proliferation assay were identified. Preliminary SAR information showed that the isonitrile group is essential for the observed activity against the Dd2 strain and the bis-isonitrile compounds in general perform better than the corresponding mono-isonitrile compounds.

Cryoballoon versus radiofrequency ablation for paroxysmal atrial fibrillation in hemodialysis patients.

INTRODUCTION: Little evidence exists regarding cryoballoon ablation (CBA) of paroxysmal atrial fibrillation (PAF) in hemodialysis (HD) patients. We compared CBA and radiofrequency ablation (RFA) of PAF in HD patients, referring to CBA of PAF in non-HD patients. METHODS AND RESULTS: This historical cohort study examined 88 patients who underwent catheter ablation of PAF, including 21 HD patients with a second-generation 28-mm cryoballoon (CB-HD group), 17 HD patients with a non-force-sensing radiofrequency catheter (RF-HD group), and 50 non-HD patients with a cryoballoon (CB-non-HD group). Pulmonary vein (PV) isolation alone aside from cavotricuspid isthmus ablation was performed in 14 (67%) in the CB-HD group, 12 (71%) in the RF-HD group, and 36 (72%) in the CB-non-HD group (P = 0.95), without isoproterenol-induced non-PV triggers. Non-PV trigger ablation was added to the other patients. The Kaplan-Meier estimated 1-year freedom from atrial tachyarrhythmia recurrence without antiarrhythmic drugs after a single procedure was 76%, 59%, and, 92% in the CB-HD, RF-HD, and CB-non-HD groups, respectively (P = 0.002). The mean procedure time was shorter in the CB-HD group than in the RF-HD group (127 vs. 199 min; P < 0.001). In the second procedure, the median number of reconnected pulmonary veins was 0.5 in the CB-HD group versus 2.0 in the RF-HD group (P = 0.17). CONCLUSION: For PAF in HD patients, CBA showed a comparable single-procedure efficacy to that of RFA with a short procedure time. CBA may be a reasonable initial procedure for HD patients suffering from symptomatic PAF.

Targeting Plasmodium PI(4)K to eliminate malaria.

Achieving the goal of malaria elimination will depend on targeting Plasmodium pathways essential across all life stages. Here we identify a lipid kinase, phosphatidylinositol-4-OH kinase (PI(4)K), as the target of imidazopyrazines, a new antimalarial compound class that inhibits the intracellular development of multiple Plasmodium species at each stage of infection in the vertebrate host. Imidazopyrazines demonstrate potent preventive, therapeutic, and transmission-blocking activity in rodent malaria models, are active against blood-stage field isolates of the major human pathogens P. falciparum and P. vivax, and inhibit liver-stage hypnozoites in the simian parasite P. cynomolgi. We show that imidazopyrazines exert their effect through inhibitory interaction with the ATP-binding pocket of PI(4)K, altering the intracellular distribution of phosphatidylinositol-4-phosphate. Collectively, our data define PI(4)K as a key Plasmodium vulnerability, opening up new avenues of target-based discovery to identify drugs with an ideal activity profile for the prevention, treatment and elimination of malaria.

Identification of Hsp90 Inhibitors with Anti-Plasmodium Activity.

Malaria remains a global health burden partly due to Plasmodium parasite resistance to first-line therapeutics. The molecular chaperone heat shock protein 90 (Hsp90) has emerged as an essential protein for blood-stage Plasmodium parasites, but details about its function during malaria's elusive liver stage are unclear. We used target-based screens to identify compounds that bind to Plasmodium falciparum and human Hsp90, which revealed insights into chemotypes with species-selective binding. Using cell-based malaria assays, we demonstrate that all identified Hsp90-binding compounds are liver- and blood-stage Plasmodium inhibitors. Additionally, the Hsp90 inhibitor SNX-0723 in combination with the phosphatidylinositol 3-kinase inhibitor PIK-75 synergistically reduces the liver-stage parasite load. Time course inhibition studies with the Hsp90 inhibitors and expression analysis support a role for Plasmodium Hsp90 in late-liver-stage parasite development. Our results suggest that Plasmodium Hsp90 is essential to liver- and blood-stage parasite infections and highlight an attractive route for development of species-selective PfHsp90 inhibitors that may act synergistically in combination therapies to prevent and treat malaria.

Synthesis of a Bicyclic Azetidine with In Vivo Antimalarial Activity Enabled by Stereospecific, Directed C(sp3)-H Arylation.

The development of new antimalarial therapeutics is necessary to address the increasing resistance to current drugs. Bicyclic azetidines targeting Plasmodium falciparum phenylalanyl-tRNA synthetase comprise one promising new class of antimalarials, especially due to their activities against three stages of the parasite's life cycle, but a lengthy synthetic route to these compounds may affect the feasibility of delivering new therapeutic agents within the cost constraints of antimalarial drugs. Here, we report an efficient synthesis of antimalarial compound BRD3914 (EC50 = 15 nM) that hinges on a Pd-catalyzed, directed C(sp3)-H arylation of azetidines at the C3 position. This newly developed protocol exhibits a broad substrate scope and provides access to valuable, stereochemically defined building blocks. BRD3914 was evaluated in P. falciparum-infected mice, providing a cure after four oral doses.

Incidence of silent cerebral infarctions after catheter ablation of atrial fibrillation utilizing the second-generation cryoballoon.

AIMS: Pulmonary vein (PV) isolation (PVI) utilizing a cryoballoon (CB) has become one of the standard therapeutic options for atrial fibrillation (AF). However, it connotes a potential risk of cerebral ischaemic events (CIEs). This study aimed to clarify the prevalence of CIEs after PVI using second-generation CBs assessed by magnetic resonance imaging (MRI) of the brain. METHODS AND RESULTS: This prospective observational study consisted of 160 patients that underwent PVI with second-generation CBs for drug-refractory AF. Irrigated radiofrequency (RF) ablation for 'touch-up' procedures was utilized when conduction gaps between the left atrium (LA) and PVs were found after the CB application. Radiofrequency linear ablation was added in select patients. Cerebral MRI and neurological examinations were performed on the day following the ablation procedure. The MRI depicted micro-cerebral infarctions in 43 patients (26.9%, 1.49 lesions per case). All patients were free from symptomatic focal neurological deficits. Touch up ablation was required for the PVI establishment in 35 patients (21.9%). Linear ablation was performed in 59 patients (36.9%). Additional RF ablation within the LA was an independent risk of CIEs in the uni- and multivariate analyses. When the analyses were limited to patients who had undergone only CB ablation, CIEs were found in 12 of 66 patients (18.2%). CONCLUSION: Pulmonary vein isolation utilizing second-generation CBs carries a negligible risk of symptomatic CIEs; however, it includes a comparable risk of asymptomatic CIEs as in the previous similar reports using the first-generation CB. Radiofrequency applications in addition to the CB within the LA were the only predictor of this adverse effect.

The Efficacy of Isochronal 3D Mapping-Based Ablation of Ventricular Arrhythmia.

Treatment of ventricular arrhythmias (VAs) commonly involves ablating sites showing electrograms with the earliest activity relative to the VA, but there is no threshold value for prematurity guaranteeing success. Ablation of sites with great prematurity can still result in failure.We hypothesized that isochronal map area (ISCA), derived from isochrones indicating electrogram prematurity, could help identify ablation targets in VA patients, as well as predict outcome. Specifically, we hypothesized that smaller ICSA for a given prematurity value would indicate a shallower arrhythmogenic focus leading to a higher likelihood of successful ablation.We studied ICSA in 29 patients (12 males, 57 [17-65] years old) undergoing VA ablation. The VAs originated from the right and left ventricles in 11 and 18 patients, respectively. The earliest activation site of the VAs, ECG morphology of sinus beats and premature ventricular complexes (PVCs), and ISCA of activation preceding PVCs were evaluated.RF ablation at the site showing earliest prematurity resulted in VA elimination in 21 patients (success group). The 5-ms ISCA was smaller in the success group than in the failure group (0.2 [0.1-0.6] versus 1.0 [0.8-1.5] cm2, respectively; P < 0.01). No significant difference was noted in prematurity itself (36 [30-45] versus 30 [29-33] ms, respectively; P = 0.07). The cut-off value of the 5 ms ISCA for successful RF ablation was 0.7 cm2 with 87.5% sensitivity and 85.6% specificity.Isochrones of activity preceding PVCs appear to contain information beyond prematurity values and may help dictate suitable areas for successful ablation of VAs.

Chemical interrogation of the malaria kinome.

Malaria, an infectious disease caused by eukaryotic parasites of the genus Plasmodium, afflicts hundreds of millions of people every year. Both the parasite and its host utilize protein kinases to regulate essential cellular processes. Bioinformatic analyses of parasite genomes predict at least 65 protein kinases, but their biological functions and therapeutic potential are largely unknown. We profiled 1358 small-molecule kinase inhibitors to evaluate the role of both the human and the malaria kinomes in Plasmodium infection of liver cells, the parasites' obligatory but transient developmental stage that precedes the symptomatic blood stage. The screen identified several small molecules that inhibit parasite load in liver cells, some with nanomolar efficacy, and each compound was subsequently assessed for activity against blood-stage malaria. Most of the screening hits inhibited both liver- and blood-stage malaria parasites, which have dissimilar gene expression profiles and infect different host cells. Evaluation of existing kinase activity profiling data for the library members suggests that several kinases are essential to malaria parasites, including cyclin-dependent kinases (CDKs), glycogen synthase kinases, and phosphoinositide-3-kinases. CDK inhibitors were found to bind to Plasmodium protein kinase 5, but it is likely that these compounds target multiple parasite kinases. The dual-stage inhibition of the identified kinase inhibitors makes them useful chemical probes and promising starting points for antimalarial development.

The utility of combining continuous wavelet transform analysis and high-density voltage map in predicting the long-term outcomes after ablation of persistent atrial fibrillation.

BACKGROUND: Continuous wavelet transform (CWT) analysis is a frequency analysis to detect areas of stable high-frequent activity (stable pseudo frequency [sPF]) during atrial fibrillation (AF). As previously reported, patients with the highest sPF area in pulmonary veins (PV) showed better short-term outcomes after PV isolation (PVI). This study sought to evaluate the efficacy of CWT analysis in predicting the long-term (2 years) outcomes after PVI. We also combined the left atrial (LA) voltage map with CWT analysis to further predict the outcome. METHODS: Persistent AF patients (n = 109, age 65 ± 10) underwent a CWT analysis at PVs and 8 LA sites during AF for pre-PVI analysis. After PVI during AF, CWT analysis was performed again in the LA as post-PVI analysis and was compared with pre-PVI analysis. A sinus voltage map of LA was created after cardioversion. RESULTS: Seventy patients had the highest sPF within PVs (PV-dominant group), while 39 patients had the highest sPF outside PVs (LA-dominant group). The global frequency in the LA showed a significant decrease after PVI only in PV-dominant group (6.55 ± 0.27 to 6.43 ± 0.37, P < 0.01). AF-free survival was better in PV-dominant group than LA-dominant group at 2-year follow-up (87.1% vs. 64.3%, P < 0.002). This trend was recognized throughout all degrees of low voltage area in the LA (LA-LVA), and AF-free survival was well predicted by combining CWT analysis and LA-LVA. CONCLUSIONS: By combining CWT analysis and sinus LA-LVA, the long-term AF-free survival after PVI was well stratified and predicted.

Risk prediction of inappropriate implantable cardioverter-defibrillator therapy using machine learning.

We aimed to develop machine learning-based predictive models for identifying inappropriate implantable cardioverter-defibrillator (ICD) therapy. Our study included 182 consecutive cases (average age 62.2 ± 4.5 years, 169 men) and employed 14 non-deep learning models for prediction (hold-out method). These models utilized selected electrocardiogram parameters and clinical features collected after ICD implantation. From the feature importance analysis of the best ML model, we established easily calculable scores. Among the patients, 25 (13.7%) experienced inappropriate therapy, and we identified 16 significant predictors. Using recursive feature elimination with cross-validation, we reduced the features to six with high feature importance: history of atrial arrhythmia (Atr-arrhythm), ischemic cardiomyopathy (ICM), absence of diabetes mellitus (DM), lack of cardiac resynchronization therapy (CRT), V3 ST level at J point (V3 STJ), and V5 R-wave amplitudes (V5R amp). The extra-trees classifier yielded the highest area under receiver operating characteristics curve (AUROC; 0.869 on test data). Thus, the Cardi35 score was defined as [+ 5.5*Atr-arrhythm - 1.5*CRT + 1.0*V3STJ + 1.0*V5R - 1.0*ICM - 0.5*DM], which demonstrated a hazard ratio of 1.62 (P < 0.001). A cut-off value of the score + 5.5 showed high AUROC (0.826). The ML approach can yield a robust prediction model, and the Cardi35 score was a convenient predictor for inappropriate therapy.

Cytoplasmic isoleucyl tRNA synthetase as an attractive multistage antimalarial drug target.

Development of antimalarial compounds into clinical candidates remains costly and arduous without detailed knowledge of the target. As resistance increases and treatment options at various stages of disease are limited, it is critical to identify multistage drug targets that are readily interrogated in biochemical assays. Whole-genome sequencing of 18 parasite clones evolved using thienopyrimidine compounds with submicromolar, rapid-killing, pan-life cycle antiparasitic activity showed that all had acquired mutations in the P. falciparum cytoplasmic isoleucyl tRNA synthetase (cIRS). Engineering two of the mutations into drug-naïve parasites recapitulated the resistance phenotype, and parasites with conditional knockdowns of cIRS became hypersensitive to two thienopyrimidines. Purified recombinant P. vivax cIRS inhibition, cross-resistance, and biochemical assays indicated a noncompetitive, allosteric binding site that is distinct from that of known cIRS inhibitors mupirocin and reveromycin A. Our data show that Plasmodium cIRS is an important chemically and genetically validated target for next-generation medicines for malaria.

Symptomatic periesophageal vagal nerve injury by different energy sources during atrial fibrillation ablation.

Background: Symptomatic gastric hypomotility (SGH) is a rare but major complication of atrial fibrillation (AF) ablation, but data on this are scarce. Objective: We compared the clinical course of SGH occurring with different energy sources. Methods: This multicenter study retrospectively collected the characteristics and clinical outcomes of patients with SGH after AF ablation. Results: The data of 93 patients (67.0 ± 11.2 years, 68 men, 52 paroxysmal AF) with SGH after AF ablation were collected from 23 cardiovascular centers. Left atrial (LA) ablation sets included pulmonary vein isolation (PVI) alone, a PVI plus a roof-line, and an LA posterior wall isolation in 42 (45.2%), 11 (11.8%), and 40 (43.0%) patients, respectively. LA ablation was performed by radiofrequency ablation, cryoballoon ablation, or both in 38 (40.8%), 38 (40.8%), and 17 (18.3%) patients, respectively. SGH diagnoses were confirmed at 2 (1-4) days post-procedure, and 28 (30.1%) patients required re-hospitalizations. Fasting was required in 81 (92.0%) patients for 4 (2.5-5) days; the total hospitalization duration was 11 [7-19.8] days. After conservative treatment, symptoms disappeared in 22.3% of patients at 1 month, 48.9% at 2 months, 57.6% at 3 months, 84.6% at 6 months, and 89.7% at 12 months, however, one patient required surgery after radiofrequency ablation. Symptoms persisted for >1-year post-procedure in 7 patients. The outcomes were similar regardless of the energy source and LA lesion set. Conclusions: The clinical course of SGH was similar regardless of the energy source. The diagnosis was often delayed, and most recovered within 6 months, yet could persist for over 1 year in 10%.