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1. Because diabetic hearts have an increased threshold for cardioprotection by ischaemic preconditioning (IPC), we hypothesized that protection byl-glutamate during reperfusion is restricted in Type 2 diabetic hearts. Previously, we found thatl-glutamate-mediated postischaemic cardioprotection mimics IPC. 2. Rat hearts were studied in a Langendorff preparation perfused with Krebs’–Henseleit solution and subjected to 40 min global no-flow ischaemia, followed by 120 min reperfusion.l-Glutamate (0, 15 and 30 mmol/L) was added to the perfusate during reperfusion of hearts from non-diabetic (Wistar-Kyoto) and diabetic (Zucker diabetic fatty (ZDF)) rats, studied at 16 weeks of age. The infarct size (IS)/area-at-risk (AAR) ratio was the primary end-point. Expression ofl-glutamate excitatory amino acid transporter (EAAT) 1 (mitochondrial) and EAAT3 (sarcolemmal) was determined by quantitative polymerase chain reaction and immunoblotting. 3. The ISS/AAR ratio did not differ between control hearts from Wistar-Kyoto and ZDF rats (0.52 ± 0.03 and 0.51 ± 0.04, respectively; P = 0.90).l-Glutamate (15 mmol/L) significantly reduced the IS/AAR ratio in non-diabetic hearts, but not in diabetic hearts, compared with their respective controls. The higher concentration ofl-glutamate (30 mmol/L) reduced infarct size in diabetic hearts to the same degree as in non-diabetic hearts (IS/AAR 0.35 ± 0.03 ( P = 0.002) and 0.34 ± 0.03 ( P = 0.004), respectively). The mitochondriall-glutamate transporter EAAT1 was downregulated in hearts from ZDF rats at both the mRNA and protein levels ( P < 0.0005 and P < 0.0001, respectively). However, there was no change in EAAT3 expression at the protein level. Myocardiall-glutamate content was increased by 43% in diabetic hearts ( P < 0.0001). 4. Hearts from obese diabetic rats have an elevated threshold for metabolic postischaemic cardioprotection byl-glutamate. These findings may reflect underlying mechanisms of inherent resistance against additional cardioprotection in the diabetic heart. [ABSTRACT FROM AUTHOR]

Background: Electrogram dispersion identifies putative atrial fibrillation (AF) drivers in first time ablation procedures, with high acute termination rates and long-term outcomes akin to extensive ablation approaches. Its use in a population that had undergone repeat ablation is unknown, particularly where the pulmonary veins are already isolated., Objective: This purpose of this study was to assess electrogram dispersion mapping during repeat ablation procedures for persistent AF., Methods: One hundred sixty-seven patients from the United Kingdom and Denmark, all with persistent AF recurrence after prior ablation procedure(s), were mapped using a five splined catheter for electrogram dispersion before ablation. Areas were manually tagged on biatrial electroanatomic maps and ablated once pulmonary vein isolation was confirmed or reisolated if required. All patients had 12-month continuous monitoring, with most of the cohort having follow-up beyond 24 months., Results: Of the 167 patients [53 (32%) female; mean age 66 ± 8 years; mean left atrial (LA) diameter 4.8 cm; mean ejection fraction 53%], 108 had pulmonary veins already isolated. Dispersion sites occurred in both atria (3.2 LA, 1.4 right atrium). Acute termination to sinus rhythm occurred in 71 (42%) of the cohort patients, with a further 73 (44%) terminating to atrial tachycardia/flutter. At 12-month follow-up, 95% of patients were free of AF, with 74% overall freedom from all atrial arrhythmias. Heart failure and severely enlarged LA predicted recurrence, and termination to sinus improved freedom from all atrial arrhythmias., Conclusion: Dispersion mapping is a promising approach at repeat ablation procedures for persistent AF, with high acute termination rates and good clinical outcomes. Further prospective randomized trials are needed to evaluate this approach in a population that had undergone repeat ablation., (© 2024 Heart Rhythm Society. Published by Elsevier Inc.)

Background: Voltage mapping to detect ventricular scar is important for guiding catheter ablation, but the field-of-view of unipolar, bipolar, conventional, and microelectrodes as it relates to the extent of viable myocardium (VM) is not well defined., Objectives: The purpose of this study was to evaluate electroanatomic voltage-mapping (EAVM) with different-size electrodes for identifying VM, validated against high-resolution ex-vivo cardiac magnetic resonance (HR-LGE-CMR)., Methods: A total of 9 swine with early-reperfusion myocardial infarction were mapped with the QDOT microcatheter. HR-LGE-CMR (0.3-mm slices) were merged with EAVM. At each EAVM point, the underlying VM in multisize transmural cylinders and spheres was quantified from ex vivo CMR and related to unipolar and bipolar voltages recorded from conventional and microelectrodes., Results: In each swine, 220 mapping points (Q1, Q3: 216, 260 mapping points) were collected. Infarcts were heterogeneous and nontransmural. Unipolar and bipolar voltage increased with VM volumes from >175 mm 3 up to >525 mm 3 (equivalent to a 5-mm radius cylinder with height >6.69 mm). VM volumes in subendocardial cylinders with 1- or 3-mm depth correlated poorly with all voltages. Unipolar voltages recorded with conventional and microelectrodes were similar (difference 0.17 ± 2.66 mV) and correlated best to VM within a sphere of radius 10 and 8 mm, respectively. Distance-weighting did not improve the correlation., Conclusions: Voltage increases with transmural volume of VM but correlates poorly with small amounts of VM, which limits EAVM in defining heterogeneous scar. Microelectrodes cannot distinguish thin from thick areas of subendocardial VM. The field-of-view for unipolar recordings for microelectrodes and conventional electrodes appears to be 8 to 10 mm, respectively, and unexpectedly similar., Competing Interests: Funding Support and Author Disclosures This study was partially supported by an investigator-initiated grant from Biosense Webster (a Johnson and Johnson company). Dr Tofig has received research support from the Arvid Nilssons Foundation. Mr Leenknegt was funded by FWO-Flanders grant number G025820N and KU Leuven grant STG/19/007. Outside this work, Dr Nielsen has received research support from the Novo Nordisk Foundation (grants NNF16OC0018658 and NNF17OC0029148). Dr Lukac has received an institutional grant from Abbott Denmark and Biosense Webster. All other authors have reported that they have no relationships to disclose that are relevant to the contents of this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: In March 2018, the European pregnancy prevention programme for oral retinoids was updated as part of risk minimisation measures (RMM), emphasising their contraindication in pregnant women. Objective: To measure the impact of the 2018 revision of the RMMs in Europe by assessing the utilisation patterns of isotretinoin, alitretinoin and acitretin, contraceptive measures, pregnancy testing, discontinuation, and pregnancy occurrence concomitantly with a retinoid prescription. Methods: An interrupted time series (ITS) analysis to compare level and trend changes after the risk minimisation measures implementation was conducted on a cohort of females of childbearing age (12-55 years of age) from January 2010 to December 2020, derived from six electronic health data sources in four countries: Denmark, Netherlands, Spain, and Italy. Monthly utilisation figures (incidence rates [IR], prevalence rates [PR] and proportions) of oral retinoids were calculated, as well as discontinuation rates, contraception coverage, pregnancy testing, and rates of exposed pregnancies to oral retinoids, before and after the 2018 RMMs. Results: From 10,714,182 females of child-bearing age, 88,992 used an oral retinoid at any point during the study period (mean age 18.9-22.2 years old). We found non-significant level and trend changes in incidence or prevalence of retinoid use in females of child-bearing age after the 2018 RMMs. The reason of discontinuation was unknown in >95% of cases. Contraception use showed a significant increase trend in Spain; for other databases this information was limited. Pregnancy testing was hardly recorded thus was not possible to model ITS analyses. After the 2018 RMM, rates of pregnancy occurrence during retinoid use, and start of a retinoid during a pregnancy varied from 0.0 to 0.4, and from 0.2 to 0.8, respectively. Conclusion: This study shows a limited impact of the 2018 RMMs on oral retinoids utilisation patterns among females of child-bearing age in four European countries. Pregnancies still occur during retinoid use, and oral retinoids are still prescribed to pregnant women. Contraception and pregnancy testing information was limited in most databases. Regulators, policymakers, prescribers, and researchers must rethink implementation strategies to avoid any pregnancy becoming temporarily related to retinoid use., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Durán, Riera-Arnau, Abtahi, Pajouheshnia, Hoxhaj, Gamba, Alsina, Martin-Perez, Garcia-Poza, Llorente-Garcia, Gonzalez-Bermejo, Ibánez, Sabaté, Vidal, Ballarín, Sanfélix-Gimeno, Rodríguez-Bernal, Peiró, García-Sempere, Sanchez-Saez, Ientile, Ingrasciotta, Guarneri, Tanaglia, Tari, Herings, Houben, Swart-Polinder, Holthuis, Huerta, Gini, Roberto, Bartolini, Paoletti, Limoncella, Girardi, Hyeraci, Andersen, Kristiansen, Hallgreen, Klungel and Sturkenboom.)

Background: Abnormal cardiac innervation plays an important role in arrhythmogenicity after myocardial infarction (MI). Data regarding reperfusion models and innervation abnormalities in the medium to long term after MI are sparse. Histologic quantification of the small-sized cardiac nerves is challenging, and transmural analysis has not been performed., Objectives: This study sought to assess cardiac innervation patterns in transmural biopsy sections in a porcine reperfusion model of MI (MI-R) using a novel method for nerve quantification., Methods: Transmural biopsy sections from 4 swine (n = 83) at 3 months after MI-R and 3 controls (n = 38) were stained with picrosirius red (fibrosis) and beta-III-tubulin (autonomic nerves). Biopsy sections were classified as infarct core, border zone, or remote zone. Each biopsy section was analyzed with a custom software pipeline, allowing calculation of nerve density and classification into innervation types at the 1 × 1-mm resolution level. Relocation of the classified squares to the original biopsy position enabled transmural quantification and innervation heterogeneity assessment., Results: Coexisting hyperinnervation, hypoinnervation, and denervation were present in all transmural MI-R biopsy sections. The innervation heterogeneity was greatest in the infarct core (median: 0.14; IQR: 0.12-0.15), followed by the border zone (median: 0.05; IQR: 0.04-0.07; P = 0.02) and remote zone (median: 0.02; IQR: 0.02-0.03; P < 0.0001). Only in the border zone was a positive linear relation between fibrosis and innervation heterogeneity observed (R = 0.79; P < 0.0001)., Conclusions: This novel method allows quantification of nerve density and heterogeneity in large transmural biopsy sections. In the chronic phase after MI-R, alternating innervation patterns were identified within the same biopsy section. Persistent innervation heterogeneity, in particular in the border zone biopsy sections, may contribute to late arrhythmogenicity., Competing Interests: Funding Support and Author Disclosures Dr Jongbloed is supported by a personal research grant from NWO ZonMw (project no. 91719346), by a grant of the Dutch Bontius Stichting, and by a grant from the Rembrandt Foundation. Marco DeRuiter is funded by the Dutch Heart Foundation and by a grant of the Dutch Bontius Stichting. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Introduction: Due to established teratogenicity of valproates, the EU risk minimisation measures (RMMs) with a pregnancy prevention programme (PPP) for valproate were updated in March 2018., Objectives: To investigate the effectiveness of the 2018 EU RMMs on valproate utilisation in five European countries/regions., Methods: A multi-database, times series study of females of childbearing potential (12-55 years) was conducted using electronic medical records from five countries/regions (01.01.2010-31.12.2020): Denmark, Tuscany (Italy), Spain, the Netherlands, and the UK. Clinical and demographic information from each database was transformed to the ConcePTION Common Data Model, quality checks were conducted and a distributed analysis was performed using common scripts. Incident and prevalent use of valproate, proportion of discontinuers and switchers to alternative medicine, frequency of contraception coverage during valproate use, and occurrence of pregnancies during valproate exposure were estimated per month. Interrupted time series analyses were conducted to estimate the level or trend change in the outcome measures., Results: We included 69,533 valproate users from 9,699,371 females of childbearing potential from the five participating centres. A significant decline in prevalent use of valproates was observed in Tuscany, Italy (mean difference post-intervention -7.7%), Spain (-11.3%), and UK (-5.9%) and a non-significant decline in the Netherlands (-3.3%), but no decline in incident use after the 2018 RMMs compared to the period before. The monthly proportion of compliant valproate prescriptions/dispensings with a contraceptive coverage was low (<25%), with an increase after the 2018 RMMs only in the Netherlands (mean difference post-intervention 12%). There was no significant increase in switching rates from valproates to alternative medicine after the 2018 intervention in any of the countries/regions. We observed a substantial number of concurrent pregnancies during valproate exposure, but with a declining rate after the 2018 RMMs in Tuscany, Italy (0.70 per 1000 valproate users pre- and 0.27 post-intervention), Spain (0.48 and 0.13), the Netherlands (0.34 and 0.00), and an increasing rate in UK (1.13 and 5.07)., Conclusion: There was a small impact of the 2018 RMMs on valproate use in the studied European countries/regions. The substantial number of concurrent pregnancies with valproate exposure warrants a careful monitoring of implementation of the existing PPP for valproate in clinical practice in Europe, to see if there is any need for additional measures in the future., (© 2023. The Author(s).)

The EU Horizon 2020 Framework-funded Standardized Treatment and Outcome Platform for Stereotactic Therapy Of Re-entrant tachycardia by a Multidisciplinary (STOPSTORM) consortium has been established as a large research network for investigating STereotactic Arrhythmia Radioablation (STAR) for ventricular tachycardia (VT). The aim is to provide a pooled treatment database to evaluate patterns of practice and outcomes of STAR and finally to harmonize STAR within Europe. The consortium comprises 31 clinical and research institutions. The project is divided into nine work packages (WPs): (i) observational cohort; (ii) standardization and harmonization of target delineation; (iii) harmonized prospective cohort; (iv) quality assurance (QA); (v) analysis and evaluation; (vi, ix) ethics and regulations; and (vii, viii) project coordination and dissemination. To provide a review of current clinical STAR practice in Europe, a comprehensive questionnaire was performed at project start. The STOPSTORM Institutions' experience in VT catheter ablation (83% ≥ 20 ann.) and stereotactic body radiotherapy (59% > 200 ann.) was adequate, and 84 STAR treatments were performed until project launch, while 8/22 centres already recruited VT patients in national clinical trials. The majority currently base their target definition on mapping during VT (96%) and/or pace mapping (75%), reduced voltage areas (63%), or late ventricular potentials (75%) during sinus rhythm. The majority currently apply a single-fraction dose of 25 Gy while planning techniques and dose prescription methods vary greatly. The current clinical STAR practice in the STOPSTORM consortium highlights potential areas of optimization and harmonization for substrate mapping, target delineation, motion management, dosimetry, and QA, which will be addressed in the various WPs., Competing Interests: Conflict of interests: D.K. has received honoraria from Merck Sharp & Dohme and Pfizer, as well as research funding from Merck KGaA, all outside of the submitted work. M.A. is a consultant for Biosense Webster and Boston Scientific, has received educational grants from Abbott, and is a proctor for Medtronic. J.B.-H. received personal fees from EBAMed SA, Switzerland, outside the submitted work. O.E. received honoraries for participation on advisory board meetings from Merck Serono, MSD, and AstraZeneca concerning oncologic treatments and also received project funding for clinical trials from non-profit organizations, all outside of the submitted work. T.R. gets research grants from the Swiss National Science Foundation, the Swiss Heart Foundation, and the Sitem Insel support fund. Speaker/consulting honoraria or travel support from Abbott/SJM, Bayer, Biosense Webster, Biotronik, Boston Scientific, Daiichi Sankyo, Farapulse, Medtronic, and Pfizer-BMS. Support for the institution’s fellowship programme from Abbott/SJM, Biosense Webster, Biotronik, Boston Scientific and Medtronic. A.S. received educational grants through his institution from Abbott, Bayer Healthcare, Biosense Webster, Biotronik, Boston Scientific, BMS/Pfizer, and Medtronic; and speaker/advisory board fees from Abbott, Bayer Healthcare, Daiichi Sankyo, Medtronic and Novartis. All other authors declare no conflict of interests., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Aim .To validate the National Danish Ablation Database (NDAD) by investigating to what extent data in NDAD correspond to medical records. Type of study . Non-blinded, registry-based, retrospective, validation study. Material and methods . A sample of patients who underwent ablation for atrial fibrillation in Denmark between 1 January 2016 and 31 December 2016 were included. By utilizing medical records as gold standard, positive predictive (PPV) and negative predictive values (NPV) for NDAD were assessed and presented as five main categories: arrhythmia characteristics, demographics, cardiac history, complications, and medication. PPV's and NPV's exceeding 90% were considered as high agreement. Results . 597 patients (71.0% males) were included in the study. Median age was 63.1 (IQR: 54.9-68.4) years. The median PPV and NPV estimates across all variables were respectively 90.4% (95% CI: 68%-95.2%) (PPV) and 99.4% (95% CI: 98.4%-99.8%) (NPV) at baseline, and 91.7% (95% CI: 67.4%-95.4%) (PPV) and 99.3% (98.2%-99.3%) (NPV) at follow-up. Conclusion . The data registered in NDAD agrees to a great extent with the patients' medical records, suggesting NDAD is a database with high validity. As a result of low complication rate, the PPV- and NPV-estimates among complication variables were prone to somewhat greater uncertainty compared to the rest.

Background: There is currently conflicting evidence of the association between the use of selective serotonin reuptake inhibitors (SSRIs) and acute pancreatitis. The SSRI fluoxetine has been suspected to be the driver of this serious outcome. Therefore, this study aims to investigate the potential association between fluoxetine use and the occurrence of acute pancreatitis., Methods: We conducted a nationwide cohort study using Danish register-based data from 1996 to 2016. The exposed group were new users of fluoxetine (1-year washout). The control subjects were new users of citalopram or SSRIs, excluding fluoxetine. The outcome was an incident diagnosis of acute pancreatitis with a 5-year washout. We used an intention-to-treat approach following patients for a maximum of 6 months. Cox regression analyses were performed, estimating hazard ratios (HRs) and 95% confidence intervals (CIs) adjusted for age/sex, comorbidities and co-medications, using propensity score adjustment and matching., Results: In the propensity score-matched analyses, 61 783 fluoxetine users were included. The incidence rates among users of fluoxetine and other SSRIs were 5.33 (3.05-8.66) and 5.36 (3.06-8.70) per 10 000 person-years, respectively. No increased risk of acute pancreatitis was identified following fluoxetine exposure compared with either citalopram [HR 1.00, 95% CI 0.50-2.00) or other SSRIs (0.76, 0.40-1.46)., Conclusions: Fluoxetine use was not associated with an increased risk of acute pancreatitis compared with citalopram or other SSRIs. The absolute risk of acute pancreatitis was low and did not vary between different SSRIs. Further research is needed to determine whether there is a class effect on the risk of acute pancreatitis., (© The Author(s) 2022. Published by Oxford University Press on behalf of the International Epidemiological Association.)

Introduction: Regulatory advisories on hydroxyzine and risk of QT prolongation and Torsade de pointes (TdP) were issued in the UK in April 2015 and Canada in June 2016. We hypothesized patients with risk factors for QT prolongation and TdP, compared with those without risk factors, would be less likely to initiate hydroxyzine in the UK and in British Columbia (BC), Canada, following advisories., Methods: We conducted a longitudinal study with repeated measures, and evaluated hydroxyzine initiation in a UK cohort and a concurrent BC control cohort (April 2013-March 2016) as well as in a BC advisory cohort (June 2014-May 2017)., Results: This study included 247,665 patients in the UK cohort, 297,147 patients in the BC control cohort, and 303,653 patients in the BC advisory cohort. Over a 12-month post-advisory period, hydroxyzine initiation decreased by 21% in the UK (rate ratio 0.79, 95% confidence interval 0.66-0.96) relative to the expected level of initiation based on the pre-advisory trend. Hydroxyzine initiation did not change in the BC control cohort or following the Canadian advisory in the BC advisory cohort. The decrease in hydroxyzine initiation in the UK in the 12 months after the advisories was not significantly different for patients with risk factors compared with those without risk factors., Conclusion: Hydroxyzine initiation decreased in the UK, but not in BC, in the 12 months following safety advisories. The decrease in hydroxyzine initiation in the UK was not significantly different for patients with versus without risk factors for QT prolongation and TdP., (© 2022. The Author(s).)

Objectives: This study sought to evaluate the ability of uni- and bipolar electrograms collected with a multielectrode catheter with smaller electrodes to: 1) delineate scar; and 2) determine local scar complexity., Background: Early reperfusion results in variable endocardial scar, often overlaid with surviving viable myocardium. Although bipolar voltage (BV) mapping is considered the pillar of substrate-based ablation, the role of unipolar voltage (UV) mapping has not been sufficiently explored. It has been suggested that bipolar electrograms collected with small electrode catheters can better identify complex scar geometries., Methods: Twelve swine with early reperfusion infarctions were mapped with the 48-electrode OctaRay catheter and a conventional catheter during sinus rhythm. BV electrograms with double components were identified. Transmural (n = 933) biopsy specimens corresponding to mapping points were obtained, histologically assessed, and classified by scar geometry., Results: OctaRay UV (UV Octa ) and BV (BV Octa ) amplitude were associated with the amount of viable myocardium at a given location, with a stronger association for UV Octa (R 2  = 0.767 vs 0.473). Cutoff values of 3.7 mV and 1.0 mV could delineate scar (area under the curve: 0.803 and 0.728 for UV Octa and BV Octa , respectively). The morphology of bipolar electrograms collected with the OctaRay catheter more frequently identified areas with 2 layers of surviving myocardium than electrograms collected with the conventional catheter (84% vs 71%)., Conclusions: UV mapping can generate a map to delineate the area of interest when using a multielectrode catheter. Within this area of interest, the morphology of bipolar electrograms can identify areas in which a surviving epicardial layer may overlay a poorly coupled, potentially arrhythmogenic, endocardium., Competing Interests: Funding Support and Author Disclosures This study was partially supported by a research grant from Biosense Webster Inc (a Johnson & Johnson company). Dr Tofig was supported by the Arvid Nilssons Foundation. The authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2022 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Contact force (CF)-guided catheter ablation (CA) is a novel technology developed to improve efficacy and reduce complications. In a randomised controlled trial (RCT), we previously documented that after 3 months, rate of persistent conduction block was similar with and without using CF while performing CA for typical atrial flutter (AFL). Clinical effect of CF on recurrent arrhythmia is unknown. Our objective is to study recurrent atrial arrhythmia during 12-month follow-up in a RCT investigating whether CF-guided CA for typical AFL is superior to CF-blinded CA., Methods: Patients were randomised 1:1 to CA guided by CF (intervention group) or blinded to CF (control group). After 12 months, patients attended clinical check-up preceded by a 5-day ambulatory Holter monitor recording. Primary outcome was any recurrent atrial arrhythmia ≥ 30 s within 12 months and documented in 12-lead ECG or Holter monitor recording., Results: We included 156 patients, four patients withdrew consent and two died during follow-up. Thus, 150 patients were included in final analysis. Recurrent arrhythmia was detected in 36 of 77 (47%) patients in the intervention group, and 32 of 73 patients (44%) in the control group (p = 0.51). Atrial fibrillation was detected in 23 (30%) and 29 (40%) patients in the intervention and control groups respectively. AFL was detected in 11 (14%) and 5 (7%) patients in the intervention and control groups respectively., Conclusions: Contact force-guided ablation for typical atrial flutter does not reduce recurrent atrial arrhythmia after 12-month follow-up as compared with ablation blinded for contact force., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Objectives: To investigate complications within 30-days following first-time ablation for atrial fibrillation (AF), including a composite of cardiac tamponade, hematoma requiring intervention, stroke or death, in patients ≥ 75 years of age, compared to patients aged 65-74 years. In addition, one-year all-cause mortality and AF relapse were compared., Methods & Results: All patients receiving their first catheter ablation for AF between 2012 and 2016 were identified using Danish nationwide registries. Patients aged 65-74 years served as the reference group for patients ≥ 75 years. Relapse of AF within one year was defined as cardioversion following a three-month blanking period, re-ablation or confirmed relapse within follow-up. The composite complication outcome did not differ between the two age groups, with 39/1554 (2.8%) in patients 65-74 years of age, versus 5/199 (2.5%) in older patients (adjusted HR = 0.94), 95% CI: 0.37-2.39, P = 0.896). Patients ≥ 75 years or older had no increased hazard of death within 30 days after the procedure, with an incidence of 3/1554 (0.2%) in younger patients and 2/199 (1.0%) in patients ≥ 75 years of age (adjusted HR = 4.71, 95% CI: 0.78-28.40, P = 0.091). There was no difference in relapse of AF after one year between age groups (≥ 75 years adjusted HR = 1.00, 95% CI: 0.78-1.26, P = 0.969)., Conclusion: In patients ≥ 75 years of age selected for catheter ablation for AF, the incidence of periprocedural complications, as well as one-year freedom from AF showed no statistical difference, when compared to patients 65-74 years of age., Competing Interests: Jesper Nielsen, Kristian Kragholm, Sam Riahi, Peter Søgaard, Steen B. Kristensen, Christoffer Polcwiartek, Peter Karl Jacobsen, Anna Margrethe Thøgersen and Peter Steen Hansen have no involvements that might raise the question of bias in this study. Christian Torp Petersen has received grants for studies from Byer and Novo Nordisk, not related to the current study., (Copyright and License information: Journal of Geriatric Cardiology 2021.)

Background: A novel QDOT MICRO (Biosense Webster, Inc., Irvine, CA) catheter with optimized temperature control and microelectrodes was designed to incorporate real-time temperature sensing with contact force detection and microelectrodes to streamline ablation workflow. The QDOT-MICRO feasibility study evaluated the workflow, performance, and safety of temperature-controlled catheter ablation in patients with symptomatic paroxysmal atrial fibrillation with conventional ablation setting., Methods: This was a non-randomized, single-arm, first-in-human study. The primary outcome was pulmonary vein isolation (PVI), confirmed by entrance block after adenosine and/or isoproterenol challenge. Safety outcomes included incidences of early-onset primary adverse events (AEs) and serious adverse device effects (SADEs). Device performance was evaluated via physician survey., Results: All evaluated patients (n = 42) displayed 100% PVI. Two primary AEs (4.8%) were reported: 1 pericarditis and 1 vascular pseudoaneurysm. An additional SADE of localized infection was reported in 1 patient. No stroke, patient deaths, or other unanticipated AEs were reported. Average power delivered was 32.1±4.1 W, with a mean temperature of 40.8°C±1.6°C. Mean procedure (including 20-minute wait), fluoroscopy, and radiofrequency application times were 129.8, 6.7, and 34.0 minutes, respectively. On device performance, physicians reported overall satisfactory performance with the new catheter, with highest scores for satisfaction and usefulness of the temperature indicator., Conclusions: Initial clinical experience with the novel catheter showed 100% acute PVI success and acceptable safety and device performance in temperature-controlled ablation mode. There were no deaths, stroke, or unanticipated AEs. Fluoroscopy and procedural times were short and similar or better than reported for prior generation catheters.

Background: Local ischemic preconditioning (IPC) and remote ischemic conditioning (RIC) induced by brief periods of ischemia and reperfusion protect against ischemia-reperfusion injury., Methods: We studied the sensitivity to IR-injury and the influence of strain, age, supplier, and anesthesia upon the efficacy of IPC and RIC in 7- and 16-weeks-old Sprague-Dawley and Wistar rats from three different suppliers. The influence of sedation with a hypnorm and midazolam mixture (rodent mixture) and pentobarbiturate was compared., Results: IPC attenuated infarct size in both 7-weeks-old Sprague-Dawley (48.4 ± 17.7% vs. 20.3 ± 6.9, p < 0.001) and 7-weeks-old Wistar (55.6 ± 10.9% vs. 26.8 ± 5.0%, p < 0.001) rats. Infarct size was larger in 16-weeks-old Sprague-Dawley rats, however, IPC still lowered infarct size (78.8 ± 9.2% vs. 58.3 ± 12.3%, p < 0.01). RIC reduced infarct sizes in 7-weeks-old Sprague-Dawley (75.3 ± 11.8% vs. 58.6 ± 8.9%, p < 0.05), but not in 7-weeks-old Wistar rats (31.7 ± 17.6% and 24.0 ± 12.6%, p = 0.2). In 16-weeks-old Sprague-Dawley rats, RIC did not induce protection (76.4 ± 5.5% and 73.2 ± 14.7%, p = 0.6). However, RIC induced protection in 16-weeks-old Wistar rats (45.2 ± 8.5% vs. 14.7 ± 10.8%, p < 0.001). RIC did not reduce infarct size in 7-weeks-old Sprague-Dawley rats from Charles River (62.0 ± 13.5% and 69.4 ± 10.4% p = 0.3) or 16-weeks-old Wistar rats from Janvier (50.7 ± 11.3 and 49.2 ± 16.2, p = 0.8). There was no difference between sedation with rodent mixture or pentobarbiturate., Conclusion: The cardioprotective effect of IPC is consistent across rat strains independent of age, strain, and supplier. RIC seems to be less reproducible, but still yields protection across different rat strains. However, age, animal supplier, and anesthetics may modulate the sensitivity of IR-injury and the response to RIC., (© 2021 The Authors. Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society.)

Background: Remote ischemic conditioning (RIC) by brief periods of limb ischemia and reperfusion protects against ischemia-reperfusion injury. We studied the cardioprotective role of extracellular vesicles (EV)s released into the circulation after RIC and EV accumulation in injured myocardium., Methods: We used plasma from healthy human volunteers before and after RIC (pre-PLA and post-PLA) to evaluate the transferability of RIC. Pre- and post-RIC plasma samples were separated into an EV enriched fraction (pre-EV + and post-EV +) and an EV poor fraction (pre-EV- and post-EV-) by size exclusion chromatography. Small non-coding RNAs from pre-EV + and post-EV + were purified and profiled by NanoString Technology. Infarct size was compared in Sprague-Dawley rat hearts perfused with isolated plasma and fractions in a Langendorff model. In addition, fluorescently labeled EVs were used to assess homing in an in vivo rat model. (ClinicalTrials.gov, number: NCT03380663) RESULTS: Post-PLA reduced infarct size by 15% points compared with Pre-PLA (55 ± 4% (n = 7) vs 70 ± 6% (n = 8), p = 0.03). Post-EV + reduced infarct size by 16% points compared with pre-EV + (53 ± 15% (n = 13) vs 68 ± 12% (n = 14), p = 0.03). Post-EV- did not affect infarct size compared to pre-EV- (64 ± 3% (n = 15) and 68 ± 10% (n = 16), p > 0.99). Three miRNAs (miR-16-5p, miR-144-3p and miR-451a) that target the mTOR pathway were significantly up-regulated in the post-EV + group. Labelled EVs accumulated more intensely in the infarct area than in sham hearts., Conclusion: Cardioprotection by RIC can be mediated by circulating EVs that accumulate in injured myocardium. The underlying mechanism involves modulation of EV miRNA that may promote cell survival during reperfusion.

Objectives: This study sought to assess the relative effect of catheter, tissue, and catheter-tissue parameters, on the ability to determine the amount of viable myocardium in vivo., Background: Although multiple variables impact bipolar voltages (BVs), electrode size, interelectrode spacing, and directional dependency are of particular interest with the development of catheters incorporating mini and microelectrodes., Methods: Nine swine with early reperfusion myocardial infarctions were mapped using the QDot catheter and then remapped using a Pentaray catheter. All QDot points were matched with Pentaray points within 5 mm. The swine were sacrificed, and mapping data projected onto the heart. Transmural biopsies corresponding to mapping points were obtained, allowing a comparison of electrograms recorded by mini, micro-, and conventional electrodes with histology., Results: The conventional BV of 2,322 QDot points was 1.9 ± 1.3 mV. The largest of the 3 microelectrode BVs (BV µMax ) average 4.8 ± 3.1 mV. The difference between the largest (BV μMax ) and smallest (BV μMin ) at a given location was 53.7 ± 18.1%. The relationships between both BV μMax and BV μMin and between the conventional BV and BV μMax were positively related but with a significant spread in data, which was more pronounced for the latter. Pentaray points positively related to the BV μMax with poor fit. On histology, increasing viable myocardium increased voltage, but both the slope coefficient and fit were best for BV μMax ., Conclusions: Using histology, we could demonstrate that BV μMax is superior to identify viable myocardium compared with BV C and BV using the Pentaray catheter. The ability to simultaneously record 3 BV μ s with different orientations, for the same beat, with controllable contact and selecting BV μMax for local BV may partially compensate for wave front direction., Competing Interests: Funding Support and Author Disclosures This study was partially supported by an investigator-initiated grant from Biosense Webster (a Johnson and Johnson company). Dr. Tofig was supported by the Arvid Nilssons Foundation. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2021 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Objectives: We aimed to investigate the predictors of recurrent arrhythmia after repeated pulmonary vein isolation (PVI) performed in the era of contact force without additional substrate ablation. One of the predictors studied, ablation index (AI), incorporates power, contact force, and time in a weighted formula and is reported to predict lesion size in animals. Design . Consecutive patients ( n  = 108) undergoing repeat PVI without additional substrate modification using a contact force sensing catheter were included retrospectively at a tertiary center. All ablation points were analyzed offline. A new variable, normalized AI (AI corrected for the location of the lesion-anterior vs. posterior) was calculated. The patients were systematically followed with clinical visit and 12-lead ECG as well as review of the regional electronic patient files at 3 and 12 months after the procedure with 5-day Holter at 12 months. Results . Electrical reconnection to at least one pulmonary vein (PV) was seen in 97% of the patients. The recurrence rate was 35%. There was no recurrence in patients with nAI above 1.15 ( n  = 26). Patients with electrical reconnection of up to two PVs had a higher risk of recurrence compared with patients having electrical reconnection of three or four PVs ( p  = .003), and this risk was especially high in patients with persistent atrial fibrillation (69 [39-91]%). Conclusions . The risk of recurrence is higher in patients with ablations performed with low levels of AI and in patients with reconnection to up to two PVs. Our data may indicate the need for higher target levels of AI during repeat PVI than normally used during de-novo PVI.

Aims: Contact force (CF) sensing has emerged as a tool to guide and improve outcomes for catheter ablation (CA) for cardiac arrhythmias. The clinical benefit on patient outcomes remains unknown. To study whether CF-guided CA for typical atrial flutter (AFL) is superior to CA not guided by CF., Methods and Results: In a double-blinded controlled superiority trial, we randomized patients 1:1 to receive CA for typical AFL guided by CF (intervention group) or blinded to CF (control group). In the intervention group, a specific value of the lesion size index (LSI), estimating ablation lesions size was targeted for each ablation lesion. Patients underwent electrophysiological study (EPS) after 3 months to assess occurrence of the primary endpoint of re-conduction across the cavo-tricuspid isthmus (CTI). We included 156 patients with typical AFL, median age was 68 [interquartile range (IQR) 61-74] years and 120 (77%) patients were male. At index procedure median LSI was higher in the intervention group [6.4 (IQR 5.1-7) vs. 5.6 (IQR 4.5-6.9), P < 0.0001]. After 3 months, 126 patients (58 in intervention group) underwent EPS for primary endpoint assessment. Thirty (24%) patients had CTI re-conduction, distributed with 15 patients in each treatment group (P = 0.62). We observed no difference between treatment groups with regard to fluoroscopy, ablation, or procedure times, nor peri-procedural complications., Conclusion: Contact force-guided ablation does not reduce re-conduction across the CTI after 3 months, nor does CF-guided ablation shorten fluoroscopy, ablation, or total procedure times., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: journals.permissions@oup.com.)

Background: Cavo tricuspid isthmus ablation (CTIA) is considered an effective first-line treatment for typical atrial flutter (AFL). However, many patients develop atrial fibrillation (AF) after successful CTIA. Knowledge about recurrent arrhythmia after CTIA mainly comes from small cohort studies with limited follow-up., Objective: To describe incidences of re-ablation for AFL and ablation for AF after first-time CTIA in a nation-wide cohort., Methods: In the Danish National Ablation Registry we identified patients undergoing first-time CTIA during 2010-2016. Subsequent CTIA and AF-ablation procedures were identified until March 1st, 2018. We collected information on patient comorbidities in the Danish National Patient Registry., Results: We identified 2409 patients undergoing first-time CTIA. Median age was 66 (IQR 58-72) years, 1952 (81%) were men, and 78 (3%) patients had a history of previous ablation for AF. Acute procedural success was achieved in 2288 (95%) patients. During mean follow-up of 4.0 ± 1.7 years, 242 (10%) patients underwent CTI re-ablation and 326 (13.5%) underwent ablation for AF. Baseline characteristics associated with CTI re-ablation included prolonged procedural time, unsuccessful index CTIA, age <75 years and CHA2DS2-VASc score <2. Hypertension, history of AF-ablation, age <65 years use of a contact force sensing catheter and CHA2DS2-VASc score <2 were associated with later ablation for AF., Conclusion: In a nation-wide cohort undergoing first-time CTIA for AFL, 10% of patients underwent CTI re-ablation and 13.5% ablation for AF during mean follow-up of 4.0 ± 1.7 years. Probability of a second procedure was higher in younger patients with less comorbidities., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Aims: Contact force (CF) between radiofrequency (RF) ablation catheter and myocardium and ablation index (AI) correlates with RF lesion depth and width in normal-voltage (>1.5 mV) myocardium (NVM). We investigate the impact of CF on RF lesion depth and width in low (<0.5 mV) (LVM) and intermediate-voltage (0.5-1.5 mV) myocardium (IVM) following myocardial infarction. Correlation between RF lesion depth and width evaluated by native contrast magnetic resonance imaging (ncMRI) and gross anatomical evaluation was investigated., Methods and Results: Twelve weeks after myocardial infarction, 10 pigs underwent electroanatomical mapping and endocardial RF ablations were deployed in NVM, IVM, and LVM myocardium. In vivo ncMRI was performed before the heart was excised and subjected to gross anatomical evaluation. Ninety (82%) RF lesions were evaluated. Radiofrequency lesion depth and width were smaller in IVM and LVM compared with NVM (P < 0.001). Radiofrequency lesion depth and width correlated with CF, AI, and impedance drop in NVM (CF and AI P < 0.001) and IVM (CF and AI depths P < 0.001; CF and AI widths P < 0.05). Native contrast magnetic resonance imaging evaluated RF lesion depth and width correlated with gross anatomical depth and width (NVM and IVM P < 0.001; LVM P < 0.05)., Conclusions: Radiofrequency lesions deployed by similar duration, power and CF are smaller in IVM and LVM than in NVM. Radiofrequency lesion depth and width correlated with CF, AI, and impedance drop in NVM and IVM but not in LVM. Native contrast magnetic resonance imaging may be useful to assess RF lesion depth and width in NVM, IVM, and LVM., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2019. For permissions, please email: journals.permissions@oup.com.)

Objectives: This study sought to evaluate the value of combined electrogram (EGM) information provided by simultaneous mapping using micro- and conventional electrodes in the identification of post-myocardial infarction ventricular tachycardia substrate., Background: Ventricular tachycardias after myocardial infarction are related to scars with complex geometry. Scar delineation and ventricular tachycardia substrate identification relies on bipolar voltages (BV) and EGM characteristics. Early reperfusion therapy results in small, nontransmural scars, the details of which may not be delineated using 3.5 mm tip catheters., Methods: Nine swine with early reperfusion myocardial infarction were mapped using Biosense Webster's QDOT Micro catheter, incorporating 3 microelectrodes at the tip of the standard 3.5 mm electrode. Analysis of EGM during sinus rhythm, right ventricular pacing, and short-coupled right ventricular extrastimuli was performed. The swine were sacrificed and mapping data were projected onto the heart. Transmural biopsies (n = 196) corresponding to mapping points were obtained, allowing a head-to-head comparison of EGM recorded by micro- and conventional electrodes with histology., Results: To identify scar areas using standard electrodes, unique cutoff values of unipolar voltage <5.44 mV, BV <1.27 mV (conventional), and BV <2.84 mV (microelectrode) were identified. Combining the information provided by unipolar voltage and BV mapping, the sensitivity of scar identification was increased to 93%. Micro-EGM were better able to distinguish small near-fields corresponding to a layer of viable subendocardium than conventional EGM were., Conclusions: The combined information provided by multisize electrode mapping increases the sensitivity with which areas of scar are identified. EGM from microelectrodes, with narrower spacing, allow identification of near-fields arising from thin subendocardial layer and layers activated with short delay obscured in EGM from conventional mapping catheter., (Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Objectives. Left atrial flutter has been reported in up to 10% of patients following pulmonary vein isolation or cardiac surgery. Left atrial flutter is typically highly symptomatic, responds poorly to medical antiarrhythmic treatment, and is often treated by catheter ablation. We aimed to investigate midterm freedom from recurrent arrhythmia after catheter ablation for left atrial flutter. Design . In the National Danish Ablation Registry, we identified consecutive patients, who had undergone catheter ablation for left atrial flutter between 1 January 2014 and 1 April 2017 at our centre. Results. A total of 53 patients (median age 68 years (IQR 60-71) 37 (70%) male) were included. Forty-two patients had prior left atrial catheter ablation procedures (79%), one patient prior ablation for classic atrial flutter (2%), four patients had prior surgery for congenital heart disease (8%), and six patients (11%) had no previous cardiac intervention. Acute procedural success, defined as non-inducibility of any atrial arrhythmia, was achieved in 45 of 53 patients (85%). During midterm follow-up (mean 20 ± 12 months), 26 patients experienced an episode of recurrent atrial arrhythmia. Median EHRA-score was 3 (range 2-4) before catheter ablation and reduced to median 1 (range 1-3) evaluated at follow-up visits after three and twelve months (both p  < .001, Wilcoxon rank test). Conclusion. Left atrial flutter is preceded by catheter ablation or cardiac surgery in 89% of patients. Acute procedural success is achieved in majority of patients and ablation reduces symptoms effectively. During midterm follow-up, almost half the patients experience recurrent atrial arrhythmia.

Background: The mechanisms underlying increased mortality in patients with diabetes and admission hyperglycemia after an acute coronary syndrome may involve reduced capacity for cardioprotection. We investigated the impact of hyperglycemia on exogenously activated cardioprotection by ischemic preconditioning (IPC) in hearts from rats with type 2 diabetes mellitus (T2DM) that were endogenously cardioprotected by an inherent mechanism, and the involvement of myocardial glucose uptake (MGU) and myocardial O-linked β-N-acetylglucosamine (O-GlcNAc)., Methods and Results: In isolated, perfused rat hearts subjected to ischemia-reperfusion, infarct size (IS) was overall larger during hyper- ([Glucose] = 22 mmol/L]) than normoglycemia ([Glucose] = 11 mmol/L]) (p < 0.001). IS was smaller in 12-week old Zucker diabetic fatty rats with recent onset T2DM (fa/fa) than in rats without T2DM (fa/+) (n = 8 in each group) both during hyperglycemia (p < 0.05) and normoglycemia (p < 0.05). IPC (2 × 5 min cycles) reduced IS during normo- (p < 0.01 for both groups) but not during hyperglycemia independently of the presence of T2DM. During hyperglycemia, an intensified IPC stimulus (4 × 5 min cycles) reduced IS only in hearts from animals with T2DM (p < 0.05). IPC increased MGU and O-GlcNAc levels during reperfusion in animals with and without T2DM at normoglycemia (MGU: p < 0.05, O-GlcNAc: p < 0.01 for both groups) but not during hyperglycemia. Intensified IPC at hyperglycemia increased MGU (p < 0.05) and O-GlcNAc levels (p < 0.05) only in hearts from animals with T2DM., Conclusion: While the effect of IPC is reduced during hyperglycemia in rats without T2DM, endogenous cardioprotection in animals with T2DM is not influenced by hyperglycemia and the capacity for exogenous cardioprotection by IPC is preserved. MGU and O-GlcNAc levels are increased by exogenously induced cardioprotection by IPC but not by endogenous cardioprotection in animals with T2DM reflecting different underlying mechanisms by exogenous and endogenous cardioprotection.

Objectives: The purinergic system has not been investigated in detail following ischemia/reperfusion (I/R) injury in the heart. In the present study, we focus on both release and response to extracellular adenosine triphosphate (ATP). Pannexin (Panx) channels have been shown to be involved in ATP release from myocytes and can activate P2X1 and P2Y2 receptors on the coronary artery., Design: We applied a well-characterized I/R model in rats, with 24 hours of reperfusion. Panx expression in the myocardial tissue was measured with quantitative polymerase chain reaction (qPCR) and flow cytometry. ATP release was detected in situ using luminescence and the vascular response to nucleotides determined in a wire myograph., Results: Here, we show that Panx expression is increased after experimental myocardial I/R, leading to an increase in extracellular ATP release, which could be inhibited by probenecid. Functional studies revealed that the P2Y2 receptor-dependent contraction is reduced in the coronary artery after I/R, which might be a response to the increased ATP levels., Conclusion: We, therefore, conclude that the regulation of the arterial purinergic system minimizes coronary contractions following ischemia.

Objectives: The authors conducted a multicenter study of decrement-evoked potential (DEEP)-based functional ventricular tachycardia (VT) substrate modification to evaluate if such a mechanistic and physiological strategy is feasible and efficient in clinical practice and provides reduction in the VT burden., Background: Only a fraction of the myocardium targeted in current VT substrate modification procedures is involved in the initiation and perpetuation of VT. The physiological basis of the DEEP strategy for identification of areas of initiation and maintenance of VT was recently established., Methods: We included 20 consecutive patients with ischemic cardiomyopathy. During substrate mapping, fractionated and late potentials (LPs) were tagged, and an extra stimulus was performed to determine which LPs displayed decrement (DEEPs). All patients underwent DEEP-focused ablation: elimination of DEEP + further radiofrequency (RF) if VT was still inducible. Patients were followed during 6 months., Results: Patients were predominantly male (95%), and their mean age was 64.6 ± 17.1 years. Mean left ventricular ejection fraction was 33.4 ± 11.4%. Mean ablation time was 30.6 ± 20.4 min. Specificity of DEEPs to detect the isthmus of VT was better than that of LPs (0.97 [95% confidence interval [CI]: 0.95 to 0.98] vs. 0.82 [95% CI: 0.73 to 0.89]), without significant differences in terms of sensitivity (0.61 [95% CI: 0.52 to 0.69] vs. 0.60 [95% CI: 0.44 to 0.74], respectively). Fifteen of 20 (75%) patients were free of any VT after DEEP-RF at 6 months of follow-up and there was a strong reduction in VT burden compared to 6 months pre-ablation., Conclusions: In a multicenter prospective study, DEEP substrate mapping identified the functional substrate critical to the VT circuit with high specificity. DEEP-guided VT ablation, by its physiological nature, may enable greater access to focused ablation therapy for patients requiring VT treatment., (Copyright © 2018 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Objectives: Recurrent arrhythmia after pulmonary vein isolation (PVI) by radiofrequency (RF) ablation in patients with atrial fibrillation (AFIB) remains a significant challenge. Using contact force (CF) sensing ablation catheters, we aimed to identify procedure related parameters associated with recurrence after de-novo PVI in patients with AFIB., Methods: Consecutive patients undergoing a de-novo PVI procedure (n = 120, 63% paroxysmal and 37% persistent AFIB) employing a force-sensing ablation catheter were included. A clinical control including electrocardiogram and 120 hour of Holter-recording at 12-months was performed in all patients. Recurrence was defined as any documented AFIB or atrial flutter more than 30 seconds on Holter-recording after an initial blanking period of three months., Results: Recurrence occurred in 44 patients (37%). Mean CF was lower in patients with recurrent arrhythmia (22.2 ± 9.5 vs. 28.8 ± 9.3 g, p < .001). In multi-variable analyses lower mean CF (OR 0.9 (95% CI 0.8-1.0), p = .03), and higher percentage of ablation time with a CF <10 grams (OR 1.1 (95% CI 1.0-1.1), p = .004) were both associated with recurrence in two distinct models. Dragging during ablation compared with point-by-point ablation technique was associated with recurrence in both models (OR 19.2 (95% CI 2.9-130.0), p = .002, and OR 21.7 (95% CI 2.7-176.2), p = .004)., Conclusions: Low CF and dragging during ablation as compared with point-by-point ablation technique were associated with recurrent arrhythmia in patients with AFIB undergoing de-novo PVI by RF ablation.

Background: Hypoglycemia is associated with increased mortality rate in patients with diabetes. The underlying mechanisms may involve reduced myocardial tolerance to ischemia and reperfusion (IR) or reduced capacity for ischemic preconditioning (IPC). As IPC is associated with increased myocardial glucose uptake (MGU) during reperfusion, cardioprotection is linked to glucose metabolism possibly by O-linked β-N-acetylglucosamine (O-GlcNAc). We aimed to investigate the impact of hypoglycemia in hearts from animals with diabetes on myocardial IR tolerance, on the efficacy of IPC and whether modulations of MGU and O-GlcNAc levels are involved in the underlying mechanisms., Methods: In a Langendorff model using diabetic ZDF (fa/fa) and non-diabetic (fa/+) rats (n = 6-7 in each group) infarct size (IS) was evaluated after 40 min of global ischemia and 120 min reperfusion during hypoglycemia [(glucose) = 3 mmol/l] and normoglycemia [(glucose) = 11 mmol/l]. Myocardial glucose uptake and O-GlcNAc levels were evaluated during reperfusion. IPC was induced by 2 × 5 min of global ischemia prior to index ischemia., Results: IS increased in hearts from animals with (p < 0.01) and without (p < 0.01) diabetes during hypoglycemia compared to normoglycemia. IPC reduced IS during normoglycemia in both animals with (p < 0.01) and without (p < 0.01) diabetes. During hypoglycemia, however, IPC only reduced IS in hearts from animals with diabetes (p < 0.05). IPC increased MGU during reperfusion and O-GlcNAc levels in animals with diabetes during hypo- (MGU: p < 0.05, O-GlcNAc: p < 0.05) and normoglycemia (MGU: p < 0.01, O-GlcNAc: p < 0.05) and in animals without diabetes only during normoglycemia (MGU: p < 0.05, O-GlcNAc: p < 0.01)., Conclusions: Hypoglycemia increases myocardial susceptibility to IR injury in hearts from animals with and without diabetes. In contrast to hearts from animals without diabetes, the hearts from animals with diabetes are amenable to cardioprotection during hypoglycemia. In parallel with IPC induced cardioprotection, MGU and O-GlcNAc levels increase suggesting that increased MGU and O-GlcNAc levels are involved in the mechanisms of IPC.

Background: Blockage of a coronary artery, usually caused by arteriosclerosis, can lead to life threatening acute myocardial infarction. Opening with PCI (percutaneous coronary intervention), may be lifesaving, but reperfusion might exacerbate the cellular damage, and changes in the endothelium are believed to be involved in this worsened outcome., Aim: The aim of the present study was to compare endothelial dependent and independent vasodilatory effect after experimental myocardial ischemia/reperfusion (I/R)., Methods: A well-established rat model of myocardial ischemia with 24 h of reperfusion was applied, followed by a study in a wire myograph., Results: Endothelial NO dependent relaxation in response to carbachol, was sensitive to arterial depolarization, and was unaffected by I/R. In contrast, endothelial NO dependent ADPβS signalling, which was not sensitive to arterial depolarization, was significantly reduced after I/R. Following I/R, an H 2 O 2 dependent EDH induced dilation appears in response to both of the above agonists. In addition, calcitonin gene-related peptide (CGRP) induced vasodilation was reduced., Conclusion: These data show that NO dependent ADPβS induced dilation is reduced after I/R. However, there is some compensation by released H 2 O 2 causing an EDH. Combined with a loss of maximal dilation in response to CGRP, the reduced vasodilation could be an important factor in understanding the exacerbated damage after I/R., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: Acute myocardial infarction is one of the leading causes of death. It is caused by a blockage of a coronary artery leading to reduced blood flow to the myocardium and hence ischemic damage. In addition, a second wave of damage after the flow has been restored, named reperfusion injury greatly exacerbate the damage. For the latter, no medical treatment exist. In this study the aim was to characterize Ca 2+ sensitivity in coronary arteries following experimental ischemia/reperfusion injury., Methods: Arteries were isolated from hearts exposed to a well-established rat ischemia/reperfusion model. Wire myograph combined with FURA2-AM measurements was applied to study the Ca 2+ dependency of the vasoconstriction., Results: The results presented herein show that ET B receptors (R) have much weaker Ca 2+ -sensitizing effect than ET A -R and that ET B -R appear to be more dependent on Ca 2+ influx presumably through voltage-gated Ca 2+ channels (VGCC). In addition, we show that there is an increase in the stretch-induced tone after ischemia/reperfusion, and that this increase in tone is independent of the ET B -R upregulation., Conclusion: Our data support the theory that ischemia/reperfusion may induce a phenotypical shift, which includes increased evoked ET B induced contraction in the smooth muscle cell, and also a higher basal tone development which both are dependent on Ca 2+ influx through VGCCs. This is combined with alterations in the ET A calcium handling, which has a stronger dependence on Ca 2+ release from the sarcoplasmic reticulum after I/R injury., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Left ventricular (LV) remodeling following a myocardial infarction (MI) involves formation of reactive oxygen species (ROS). Paroxetine, a selective serotonin reuptake inhibitor, has an antioxidant effect in the vascular wall. We investigated whether paroxetine reduces myocardial ROS formation and LV remodeling following a MI. In a total of 32 Wistar rats, MI was induced by a 30-min ligation of the left anterior descending artery followed by 7- or 28-day reperfusion. During the 28 days of reperfusion, LV remodeling was evaluated by magnetic resonance imaging (MRI) and echocardiography (n = 20). After 28 days of reperfusion, the susceptibility to ventricular tachycardia was evaluated prior to sacrifice and histological assessment of myocyte cross-sectional area, fibrosis, and presence of myofibroblasts. Myocardial ROS formation was measured with dihydroethidium after 7 days of reperfusion in separate groups (n = 12). Diastolic LV volume, evaluated by MRI (417 ± 60 vs. 511 ± 64 µL, p < 0.05), and echocardiography (515 ± 80 vs. 596 ± 83 µL, p < 0.05) as well as diastolic LV internal diameter evaluated with echocardiography (7.2 ± 0.6 vs. 8.1 ± 0.7 mm, p < 0.05) were lower in the paroxetine group than in controls. Furthermore, myocyte cross-sectional area was reduced in the paroxetine group compared with controls (277 ± 26 vs. 354 ± 23 mm 3 , p < 0.05) and ROS formation was reduced in the remote myocardium (0.415 ± 0.19 normalized to controls, p < 0.05). However, no differences in the presence of fibrosis or myofibroblasts were observed. Finally, paroxetine reduced the susceptibility to ventricular tachycardia (induced in 2/11 vs. 6/8 rats, p < 0.05). Paroxetine treatment following MI decreases LV remodeling and susceptibility to arrhythmias, probably by reducing ROS formation.

The voltage-gated KV7 (KCNQ) potassium channels are activated by ischemia and involved in hypoxic vasodilatation. We investigated the effect of KV7 channel modulation on cardiac ischemia and reperfusion injury and its interaction with cardioprotection by ischemic preconditioning (IPC). Reverse-transcription polymerase chain reaction revealed expression of KV7.1, KV7.4, and KV7.5 in the left anterior descending rat coronary artery and all KV7 subtypes (KV7.1-KV7.5) in the left and right ventricles of the heart. Isolated hearts were subjected to no-flow global ischemia and reperfusion with and without IPC. Infarct size was quantified by 2,3,5-triphenyltetrazolium chloride staining. Two blockers of KV7 channels, XE991 [10,10-bis(4-pyridinylmethyl)-9(10H)-anthracenone] (10 µM) and linopirdine (10 µM), reduced infarct size and exerted additive infarct reduction to IPC. An opener of KV7 channels, flupirtine (10 µM) abolished infarct size reduction by IPC. Hemodynamics were measured using a catheter inserted in the left ventricle and postischemic left ventricular recovery improved in accordance with reduction of infarct size and deteriorated with increased infarct size. XE991 (10 µM) reduced coronary flow in the reperfusion phase and inhibited vasodilatation in isolated small branches of the left anterior descending coronary artery during both simulated ischemia and reoxygenation. KV7 channels are expressed in rat coronary arteries and myocardium. Inhibition of KV7 channels exerts cardioprotection and opening of KV7 channels abrogates cardioprotection by IPC. Although safety issues should be further addressed, our findings suggest a potential role for KV7 blockers in the treatment of ischemia-reperfusion injury., (Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics.)

Remote ischemic preconditioning (rIPC), induced by cycles of transient limb ischemia and reperfusion (IR), is cardioprotective. The optimal rIPC-algorithm is not established. We investigated the effect of cycle numbers and ischemia duration within each rIPC-cycle and the influence of effector organ mass on the efficacy of cardioprotection. Furthermore, the duration of the early phase of protection by rIPC was investigated. Using a tourniquet tightened at the inguinal level, we subjected C57Bl/6NTac mice to intermittent hind-limb ischemia and reperfusion. The rIPC-protocols consisted of (I) two, four, six or eight cycles, (II) 2, 5 or 10 min of ischemia in each cycle, (III) single or two hind-limb occlusions and (IV) 0.5, 1.5, 2.0 or 2.5 h intervals from rIPC to index cardiac ischemia. All rIPC algorithms were followed by 5 min of reperfusion. The hearts were subsequently exposed to 25 min of global ischemia and 60 min of reperfusion in an ex vivo Langendorff model. Cardioprotection was evaluated by infarct size and post-ischemic hemodynamic recovery. Four to six rIPC cycles yielded significant cardioprotection with no further protection by eight cycles. Ischemic cycles lasting 2 min offered the same protection as cycles of 5 min ischemia, whereas prolonged cycles lasting 10 min abrogated protection. One and two hind-limb preconditioning were equally protective. In our mouse model, the duration of protection by rIPC was 1.5 h. These findings indicate that the number and duration of cycles rather than the tissue mass exposed to rIPC determines the efficacy of rIPC.

Giraffes--the tallest extant animals on Earth--are renowned for their high central arterial blood pressure, which is necessary to secure brain perfusion. Arterial pressure may exceed 300 mmHg and has historically been attributed to an exceptionally large heart. Recently, this has been refuted by several studies demonstrating that the mass of giraffe heart is similar to that of other mammals when expressed relative to body mass. It thus remains unexplained how the normal-sized giraffe heart generates such massive arterial pressures. We hypothesized that giraffe hearts have a small intraventricular cavity and a relatively thick ventricular wall, allowing for generation of high arterial pressures at normal left ventricular wall tension. In nine anaesthetized giraffes (495±38 kg), we determined in vivo ventricular dimensions using echocardiography along with intraventricular and aortic pressures to calculate left ventricular wall stress. Cardiac output was also determined by inert gas rebreathing to provide an additional and independent estimate of stroke volume. Echocardiography and inert gas-rebreathing yielded similar cardiac outputs of 16.1±2.5 and 16.4±1.4 l min(-1), respectively. End-diastolic and end-systolic volumes were 521±61 ml and 228±42 ml, respectively, yielding an ejection fraction of 56±4% and a stroke volume of 0.59 ml kg(-1). Left ventricular circumferential wall stress was 7.83±1.76 kPa. We conclude that, relative to body mass, a small left ventricular cavity and a low stroke volume characterizes the giraffe heart. The adaptations result in typical mammalian left ventricular wall tensions, but produce a lowered cardiac output., (© 2016. Published by The Company of Biologists Ltd.)

The G protein-coupled light-sensitive receptor melanopsin is involved in non-image-forming light responses including circadian timing. The predicted secondary structure of melanopsin indicates a long cytoplasmic tail with many potential phosphorylation sites. Using bioinformatics, we identified a number of amino acids with a high probability of being phosphorylated. We generated antibodies against melanopsin phosphorylated at Ser-381 and Ser-398, respectively. The antibody specificity was verified by immunoblotting and immunohistochemical staining of HEK-293 cells expressing rat melanopsin mutated in Ser-381 or Ser-398. Using the antibody recognizing phospho-Ser-381 melanopsin, we demonstrated by immunoblotting and immunohistochemical staining in HEK-293 cells expressing rat melanopsin that the receptor is phosphorylated in this position during the dark and dephosphorylated when light is turned on. On the contrary, we found that melanopsin at Ser-398 was unphosphorylated in the dark and became phosphorylated after light stimulation. The light-induced changes in phosphorylation at both Ser-381 and Ser-398 were rapid and lasted throughout the 4-h experimental period. Furthermore, phosphorylation at Ser-381 and Ser-398 was independent of each other. The changes in phosphorylation were confirmed in vivo by immunohistochemical staining of rat retinas during light and dark. We further demonstrated that mutation of Ser-381 and Ser-398 in melanopsin-expressing HEK-293 cells affected the light-induced Ca(2+) response, which was significantly reduced as compared with wild type. Examining the light-evoked Ca(2+) response in a melanopsin Ser-381 plus Ser-398 double mutant provided evidence that the phosphorylation events were independent., (© 2014 by The American Society for Biochemistry and Molecular Biology, Inc.)

Ischemic heart disease (IHD) is characterized by an imbalance between oxygen supply and demand, most frequently caused by coronary artery disease (CAD) that reduces myocardial perfusion. In some patients, IHD is ascribed to microvascular dysfunction (MVD): microcirculatory disturbances that reduce myocardial perfusion at the level of myocardial pre-arterioles and arterioles. In a minority of cases, chest pain and reductions in myocardial flow reserve may even occur in patients without any other demonstrable systemic or cardiac disease. In this topical review, we address whether these findings might be caused by impaired myocardial oxygen extraction, caused by capillary flow disturbances further downstream. Myocardial blood flow (MBF) increases approximately linearly with oxygen utilization, but efficient oxygen extraction at high MBF values is known to depend on the parallel reduction of capillary transit time heterogeneity (CTH). Consequently, changes in capillary wall morphology or blood viscosity may impair myocardial oxygen extraction by preventing capillary flow homogenization. Indeed, a recent re-analysis of oxygen transport in tissue shows that elevated CTH can reduce tissue oxygenation by causing a functional shunt of oxygenated blood through the tissue. We review the combined effects of MBF, CTH, and tissue oxygen tension on myocardial oxygen supply. We show that as CTH increases, normal vasodilator responses must be attenuated in order to reduce the degree of functional shunting and improve blood-tissue oxygen concentration gradients to allow sufficient myocardial oxygenation. Theoretically, CTH can reach levels such that increased metabolic demands cannot be met, resulting in tissue hypoxia and angina in the absence of flow-limiting CAD or MVD. We discuss these predictions in the context of MVD, myocardial infarction, and reperfusion injury.

Aims: Post-translational modification of proteins by O-linked β-N-acetylglucosamine (O-GlcNAc) is cardioprotective but its role in cardioprotection by remote ischaemic preconditioning (rIPC) and the reduced efficacy of rIPC in type 2 diabetes mellitus is unknown. In this study we achieved mechanistic insight into the remote stimulus mediating and the target organ response eliciting the cardioprotective effect by rIPC in non-diabetic and diabetic myocardium and the influence of O-GlcNAcylation., Methods and Results: The cardioprotective capacity and the influence on myocardial O-GlcNAc levels of plasma dialysate from eight healthy volunteers and eight type 2 diabetic patients drawn before and after subjection to an rIPC stimulus were tested on human isolated atrial trabeculae subjected to ischaemia/reperfusion injury. Dialysate from healthy volunteers exposed to rIPC improved post-ischaemic haemodynamic recovery (40 ± 6 vs. 16 ± 2%; P < 0.01) and increased myocardial O-GlcNAc levels. Similar observations were made with dialysate from diabetic patients before exposure to rIPC (43 ± 3 vs. 16 ± 2%; P < 0.001) but no additional cardioprotection or further increase in O-GlcNAc levels was achieved by perfusion with dialysate after exposure to rIPC (44 ± 4 and 42 ± 5 vs. 43 ± 3%; P = 0.7). The glutamine:fructose-6-phosphate amidotransferase (GFAT) inhibitor azaserine abolished the cardioprotective effects and the increment in myocardial O-GlcNAc levels afforded by plasma from diabetic patients and healthy volunteers treated with rIPC., Conclusions: rIPC and diabetes mellitus per se influence myocardial O-GlcNAc levels through circulating humoral factors. O-GlcNAc signalling participates in mediating rIPC-induced cardioprotection and maintaining a state of inherent chronic activation of cardioprotection in diabetic myocardium, restricting it from further protection by rIPC.

Efficacy of ischemic preconditioning is decreased in animal models of type 2 diabetes mellitus while the responses in humans with diabetes are contradictory. It is unknown whether attenuation is related to decreased release of a mediating humoral cardioprotective factor or reduced ability to respond in the target tissue. The aim of the present study was to investigate the release and effect of a circulating cardioprotective factor in type 2 diabetes mellitus patients. Blood samples were drawn from nine non-diabetic subjects, eight diabetic patients without peripheral neuropathy, and eight diabetic patients with peripheral neuropathy before (control) and after a remote ischemic preconditioning (rIPC) stimulus. Blood samples were dialyzed against Krebs-Henseleit buffer and the cardioprotective effects of the dialysates were tested in rabbit hearts mounted on a Langendorff model and subjected to 30-min global ischemia and 120-min reperfusion. rIPC dialysate from non-diabetic and diabetic subjects without peripheral neuropathy reduced infarct size and improved hemodynamic recovery compared to control dialysate from non-diabetic and diabetic subjects. However, in the subgroup of diabetic patients with neuropathy the cardioprotective effect was attenuated. These findings indicate that the release mechanism involves neural pathways.

AMP-activated protein kinase (AMPK) is an enzyme which may be involved in cardioprotective mechanisms in the ischemic heart. Exercise, AICAR, and metformin, all known activators of AMPK, induce delayed cardioprotection which protects the heart against ischemia-reperfusion injury. The objective was to determine the effect of exercise, AICAR, and metformin on gene expression profile and to demonstrate possible interactions in different genes and functions. Rats were divided into either an exercise, AICAR, metformin, or control group. 3, 12, and 24 h after either a single bout of exercise training, a single injection of AICAR or a single dose of metformin, hearts were removed and gene expression profiles were analyzed in tissue from the left ventricle using Affymetrix gene chip probe arrays. Ingenuity Pathway Analysis (IPA) tool was used to analyze the regulated genes for relevant functions and diseases. Each gene chip identified up to 30,000 different probesets of which Ingenuity identified approximately up to 12,000 genes. A total of 147, 304, and 114 different genes in the left ventricle whose expressions were altered >2.0-fold were identified in the exercise, AICAR, and metformin group, respectively. Seventy eight different genes were overlapping the exercise and AICAR group at 24 h. Ingenuity identified six overlapping genes between the exercise, AICAR, and metformin groups including NR4A3, TNFRSF12A, HBB, PENK, PAP, and MAP4K4. IPA software revealed an overabundance of focus molecules in all three intervention groups involving functions related to cell death, cellular growth and proliferation, gene expression and cancer. Exercise, AICAR, and metformin regulate several genes in the rat myocardium with the majority of overlapping genes observed in the exercise and AICAR group. Changes in gene programming mainly involved inflammatory and opioid systems recognized as cardioprotective pathways. Some of these genes may represent possible candidate genes involved in the molecular mechanisms of AMPK-induced delayed PC.

Aims/hypothesis: Sulfonylureas (SUs) may impair outcome in patients with acute coronary syndrome. Most experimental studies of the myocardial effects of SU treatment are performed in non-diabetic models. We compared the effect of two widely used SUs, glibenclamide (gb) and gliclazide (gc), with high and low myocardial K(ATP) channel affinity, respectively, at therapeutic concentrations on infarct size, left ventricular (LV) function and myocardial glycogen, lactate and alanine content before and after ischaemia/reperfusion (I/R)., Methods: Non-diabetic Wistar and diabetic Goto-Kakizaki rat hearts were investigated in a Langendorff preparation. Gb (0.1 μmol/l) and gc (1.0 μmol/l) were administrated throughout the study. Infarct size was evaluated after 120 min of reperfusion. Myocardial metabolite content was measured before and after ischaemia., Results: Infarct size was smaller in diabetic hearts than in non-diabetic hearts (0.33 ± 0.03 vs 0.51 ± 0.05, p < 0.05). Gb increased infarct size (0.54 ± 0.04 vs 0.33 ± 0.03, p < 0.05) and reduced post-ischaemic LV developed pressure (60 ± 3 vs 76 ± 3 mmHg, p < 0.05) and coronary flow (4.9 ± 0.5 vs 7.1 ± 0.4 ml min(-1) g(-1), p < 0.05) in gb-treated diabetic rats compared with untreated diabetic rats. On comparing gb-treated diabetic rats with untreated diabetic rats, glycogen content was reduced before (9.1 ± 0.6 vs 13.6 ± 1.0 nmol/mg wet weight, p < 0.01) and after ischaemia (0.9 ± 0.2 vs 1.8 ± 0.2 nmol/mg wet weight, p < 0.05), and lactate (4.8 ± 0.4 vs 3.2 ± 0.3 nmol/mg wet weight, p < 0.01) and alanine (1.38 ± 0.12 vs 0.96 ± 0.09 nmol/mg wet weight, p < 0.05) contents were increased during reperfusion. Gc-treatment of diabetic and non-diabetic rats did not affect any of the measured variables., Conclusions/interpretations: Gb, but not gc, exacerbates I/R injury and deteriorates LV function in diabetic hearts. These effects of gb on diabetic hearts may be due to detrimental effects on myocardial carbohydrate metabolism.