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Background: Revascularization of left main coronary artery (LMCA) stenosis is mostly based on angiography. Indices based on angiography might increase accuracy of the decision, although they have been scarcely used in LMCA. The objective of this study is to study the diagnostic agreement of QFR (quantitative flow ratio) with wire-based fractional flow reserve (FFR) in LMCA lesions and to compare with visual severity assessment., Methods: In a series of patients with invasive FFR assessment of intermediate LMCA stenoses we retrospectively compared the measured value of QFR with that of FFR and the estimate of significance from angiography., Results: 107 QFR studies were included. The QFR intra-observer and inter-observer agreement was 87% and 82% respectively. The mean QFR-FFR difference was 0.047 ± 0.05 with a concordance of 90.7%, sensitivity 88.1%, specificity 92.3%, positive predictive value 88.1% and negative predictive value 92.3%. All these values were superior to those observed with the visual estimation which showed an intra- and inter-observer agreement of 73% and 72% respectively, besides 78% with the FFR value. The low diagnostic performance of the visual estimation and the acceptable performance of the QFR index measurement were observed in all subgroups analysed., Conclusions: QFR allows an acceptable estimate of the FFR obtained with intracoronary pressure guidewire in intermediate LMCA lesions, and clearly superior to the assessment based on angiography alone. The decision to revascularize patients with moderate LMCA lesions should not be based solely on the degree of angiographic stenosis., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: It is unknown whether the availability of long drug-eluting stents modify the PCI strategy of long CTO. To describe the contemporary PCI strategy of long chronic total occlusions (CTO) using overlapping (OS) or single long stents (SS) and to analyze its results., Methods: 2842 consecutive CTO PCIs were included. Those with an occlusion length ≥20 mm in which ≥1 drug eluting stent (DES) was implanted were analyzed. We compared procedural characteristics and clinical outcomes of CTO treated with OS or SS., Results: 1088 CTO PCIs were analyzed (79.9% males; 64.7±10.6 years). Mean J-score was 2.8±0.9. A SS was used in 38.5% of cases and OS in 61.5%. Total stent length was 64.1±29.9 mm; it was higher in the OS group (OS: 79.9±25.5 mm vs. SS: 38.3±14.7 mm; P<0.0001). Mean number of stents in the OS group was 2.3±1. Very long stents (≥40 mm) were used in 27.4% of cases, more frequently in the OS group (OS:32.4% vs. SS:19.3%; P<0.0001). After a mean follow-up of 19±15.9 months, the rate of adverse events (MACE) was 2% (cardiac death: 1.6%, myocardial infarction: 1.6%, target lesion revascularization: 1.9% and stent thrombosis: 0.18%) with no significant differences between both groups. Overlapping was not an independent predictor of MACE., Conclusions: In long CTO PCIs, OS is more frequently used than single stenting, especially in more complex procedures. Clinical outcomes at a mid-term follow-up are favorable. Using newer generation DES, overlapping was not an independent predictor of MACE; however, a trend toward a higher event rate was observed in the OS group.

Introduction and Objectives: Severe calcification is present in> 50% of coronary chronic total occlusions (CTOs) undergoing percutaneous intervention. We aimed to describe the contemporary use and outcomes of plaque modification devices (PMDs) in this context., Methods: Patients were included in the prospective, consecutive Iberian CTO registry (32 centers in Spain and Portugal), from 2015 to 2020. Comparison was performed according to the use of PMDs., Results: Among 2235 patients, wire crossing was achieved in 1900 patients and PMDs were used in 134 patients (7%), requiring more than 1 PMD in 24 patients (1%). The selected PMDs were rotational atherectomy (35.1%), lithotripsy (5.2%), laser (11.2%), cutting/scoring balloons (27.6%), OPN balloons (2.9%), or a combination of PMDs (18%). PMDs were used in older patients, with greater cardiovascular burden, and higher Syntax and J-CTO scores. This greater complexity was associated with longer procedural time but similar total stent length (52 vs 57mm; P=.105). If the wire crossed, the procedural success rate was 87.2% but increased to 96.3% when PMDs were used (P=.001). Conversely, PMDs were not associated with a higher rate of procedural complications (3.7 vs 3.2%; P=.615). Despite the worse baseline profile, at 2 years of follow-up there were no differences in the survival rate (PMDs: 94.3% vs no-PMDs: 94.3%, respectively; P=.967)., Conclusions: Following successful wire crossing in CTOs, PMDs were used in 7% of the lesions with an increased success rate. Mid-term outcomes were comparable despite their worse baseline profile, suggesting that broader use of PMDs in this setting might have potential technical and prognostic benefits., (Copyright © 2021 Sociedad Española de Cardiología. Published by Elsevier España, S.L.U. All rights reserved.)

Brugada syndrome (BrS) is a cardiac arrhythmia disorder associated with sudden death in young adults. With the exception of SCN5A, encoding the cardiac sodium channel Na V 1.5, susceptibility genes remain largely unknown. Here we performed a genome-wide association meta-analysis comprising 2,820 unrelated cases with BrS and 10,001 controls, and identified 21 association signals at 12 loci (10 new). Single nucleotide polymorphism (SNP)-heritability estimates indicate a strong polygenic influence. Polygenic risk score analyses based on the 21 susceptibility variants demonstrate varying cumulative contribution of common risk alleles among different patient subgroups, as well as genetic associations with cardiac electrical traits and disorders in the general population. The predominance of cardiac transcription factor loci indicates that transcriptional regulation is a key feature of BrS pathogenesis. Furthermore, functional studies conducted on MAPRE2, encoding the microtubule plus-end binding protein EB2, point to microtubule-related trafficking effects on Na V 1.5 expression as a new underlying molecular mechanism. Taken together, these findings broaden our understanding of the genetic architecture of BrS and provide new insights into its molecular underpinnings., (© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Multisystem inflammatory syndrome in children (MIS-C) presents with fever, inflammation and pathology of multiple organs in individuals under 21 years of age in the weeks following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Although an autoimmune pathogenesis has been proposed, the genes, pathways and cell types causal to this new disease remain unknown. Here we perform RNA sequencing of blood from patients with MIS-C and controls to find disease-associated genes clustered in a co-expression module annotated to CD56 dim CD57 + natural killer (NK) cells and exhausted CD8 + T cells. A similar transcriptome signature is replicated in an independent cohort of Kawasaki disease (KD), the related condition after which MIS-C was initially named. Probing a probabilistic causal network previously constructed from over 1,000 blood transcriptomes both validates the structure of this module and reveals nine key regulators, including TBX21, a central coordinator of exhausted CD8 + T cell differentiation. Together, this unbiased, transcriptome-wide survey implicates downregulation of NK cells and cytotoxic T cell exhaustion in the pathogenesis of MIS-C., (© 2021. The Author(s).)

Background: We aimed to compare the performance of the recent CASTLE score to J-CTO, CL and PROGRESS CTO scores in a comprehensive database of percutaneous coronary intervention of chronic total occlusion procedures., Methods: Scores were calculated using raw data from 1,342 chronic total occlusion procedures included in REBECO Registry that includes learning and expert operators. Calibration, discrimination and reclassification were evaluated and compared., Results: Mean score values were: CASTLE 1.60±1.10, J-CTO 2.15±1.24, PROGRESS 1.68±0.94 and CL 2.52±1.52 points. The overall percutaneous coronary intervention success rate was 77.8%. Calibration was good for CASTLE and CL, but not for J-CTO or PROGRESS scores. Discrimination: the area under the curve (AUC) of CASTLE (0.633) was significantly higher than PROGRESS (0.557) and similar to J-CTO (0.628) and CL (0.652). Reclassification: CASTLE, as assessed by integrated discrimination improvement, was superior to PROGRESS (integrated discrimination improvement +0.036, p<0.001), similar to J-CTO and slightly inferior to CL score (- 0.011, p = 0.004). Regarding net reclassification improvement, CASTLE reclassified better than PROGRESS (overall continuous net reclassification improvement 0.379, p<0.001) in roughly 20% of cases., Conclusion: Procedural percutaneous coronary intervention difficulty is not consistently depicted by available chronic total occlusion scores and is influenced by the characteristics of each chronic total occlusion cohort. In our study population, including expert and learning operators, the CASTLE score had slightly better overall performance along with CL score. However, we found only intermediate performance in the c-statistic predicting chronic total occlusion success among all scores., Competing Interests: Abbott provided an unrestricted grant to support the Registry and this publication’s fees. There are no patents, products in development or marketed products associated with this research to declare. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Objectives: The goal of this study was to develop a risk score model for patients with Brugada syndrome (BrS)., Background: Risk stratification in BrS is a significant challenge due to the low event rates and conflicting evidence., Methods: A multicenter international cohort of patients with BrS and no previous cardiac arrest was used to evaluate the role of 16 proposed clinical or electrocardiogram (ECG) markers in predicting ventricular arrhythmias (VAs)/sudden cardiac death (SCD) during follow-up. Predictive markers were incorporated into a risk score model, and this model was validated by using out-of-sample cross-validation., Results: A total of 1,110 patients with BrS from 16 centers in 8 countries were included (mean age 51.8 ± 13.6 years; 71.8% male). Median follow-up was 5.33 years; 114 patients had VA/SCD (10.3%) with an annual event rate of 1.5%. Of the 16 proposed risk factors, probable arrhythmia-related syncope (hazard ratio [HR]: 3.71; p < 0.001), spontaneous type 1 ECG (HR: 3.80; p < 0.001), early repolarization (HR: 3.42; p < 0.001), and a type 1 Brugada ECG pattern in peripheral leads (HR: 2.33; p < 0.001) were associated with a higher risk of VA/SCD. A risk score model incorporating these factors revealed a sensitivity of 71.2% (95% confidence interval: 61.5% to 84.6%) and a specificity of 80.2% (95% confidence interval: 75.7% to 82.3%) in predicting VA/SCD at 5 years. Calibration plots showed a mean prediction error of 1.2%. The model was effectively validated by using out-of-sample cross-validation according to country., Conclusions: This multicenter study identified 4 risk factors for VA/SCD in a primary prevention BrS population. A risk score model was generated to quantify risk of VA/SCD in BrS and inform implantable cardioverter-defibrillator prescription., Competing Interests: Funding Support and Author Disclosures Dr. Lambiase is supported by the Stephen Lyness Memorial Fund, UCLH Biomedicine National Institutes of Health Research, Barts Biomedical Research Centre; and has obtained research grants and speaker fees from Medtronic, Abbott, and Boston Scientific. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

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Introduction and Objectives: There is current controversy regarding the benefits of percutaneous recanalization (PCI) of chronic total coronary occlusions (CTO). Our aim was to determine acute and follow-up outcomes in our setting., Methods: Two-year prospective registry of consecutive patients undergoing PCI of CTO in 24 centers., Results: A total of 1000 PCIs of CTO were performed in 952 patients. Most were symptomatic (81.5%), with chronic ischemic heart disease (59.2%). Previous recanalization attempts had been made in 15%. The mean SYNTAX score was 19.5 ± 10.6 and J-score was > 2 in 17.3%. A retrograde procedure was performed in 92 patients (9.2%). The success rate was 74.9% and was higher in patients without previous attempts (82.2% vs 75.2%; P = .001), those with a J-score ≤ 2 (80.5% vs 69.5%; P = .002), and in intravascular ultrasound-guided PCI (89.9% vs 76.2%, P = .001), which was an independent predictor of success. In contrast, severe calcification, length > 20mm, and blunt proximal cap were independent predictors of failed recanalization. The rate of procedural complications was 7.1%, including perforation (3%), myocardial infarction (1.3%), and death (0.5%). At 1-year of follow-up, 88.2% of successfully revascularized patients showed clinical improvement (vs 34.8%, P < .001), which was associated with lower mortality. At 1-year of follow-up, the mortality rate was 1.5%., Conclusions: Compared with other national registries, patients in the Iberian registry undergoing PCI of a CTO showed similar complexity, success rate, and complications. Successful recanalization was strongly associated with functional improvement, which was related to lower mortality., (Copyright © 2018. Published by Elsevier España, S.L.U.)

Introduction: According to current practice guidelines, coronary bypass surgery is the standard care option for unprotected left main (ULM) stenosis. However, a group of high surgical risk patients who are not eligible for coronary bypass surgery could benefit from percutaneous coronary intervention (PCI). Severe calcification hampers PCI in this setting, and rotational atherectomy (RA) could be of great help., Methods: We retrospectively analyzed a cohort of 40 patients with severely calcified ULM stenosis, not eligible for coronary artery bypass grafting, who underwent RA in our center., Results: Forty patients (mean age, 73 ± 8 years; 26 males) with ULM stenosis were treated with RA. Twenty-seven (67%) had distal stenosis. The mean number of treated vessels was 2.38 ± 0.74, with a mean lesion length of 30 ± 18 mm. Abciximab was used in 12 (30%) cases and an intra-aortic balloon pump in three cases. One patient died during the procedure and another two patients died in the first 24 hr after the procedure. The major events registered after the procedure included one significant branch loss, and two minor and one major case of bleeding (the latter requiring transfusion) at the puncture point. After a median of 24.7 (IQR 19.6-34.3) months of follow-up, 12 cardiac deaths were recorded. Survival free of cardiac death was 71 ± 7% and clinical guided target vessel revascularization 19.3 ± 7% at 2 years., Conclusion: In a group of high surgical risk patients, RA on severely calcified left main stenosis is feasible and, in spite of high mortality rates, could pose the only possible effective treatment., (Copyright © 2012 Wiley Periodicals, Inc.)

American Foulbrood (AFB) caused by the spore-forming bacterium Paenibacillus larvae is the most serious disease of bacterial origin affecting larvae and pupae of honeybees. Antibiotics are used in many countries for the control of AFB in high incidence areas, but their misuse may lead to antibiotic resistance of bacterial strains and honey contamination. The objective of the present work was to determine, through a biological method, the protein binding of tylosin, tilmicosin and oxytetracycline to worker jelly; honey; pollen; adult bees and larvae in order to propose their kinetic routes. The sensitivity limit of the technique used was 0.05 μg/ml for tylosin and tilmicosin and 0.01 μg/ml for oxytetracycline, respectively. The method had intra and inter-assay correlation coefficients over 0.90, respectively and a coefficient variation of intra-and inter-assay for all antibiotics and processed samples under 5%. Tylosin and oxytetracycline presented lower percentages of protein binding in tissues and hive products (average 15%) in relation to those observed for tilmicosin (29%). In conclusion, tylosin is useful for AFB control in honey bee colonies due to its chemical characteristics, antimicrobial activity and levels of protein binding in bees, larvae, and beehive products.

Introduction and Objectives: Cardiomyopathy and channelopathy are major causes of sudden death (SD). The little information available on the context in which SD occurs has come from only a few referral centers. The objective was to investigate the circumstances surrounding SD in families with inherited heart disease., Methods: The study included 152 SD patients (mean age 43+/-19 years) from 103 families. The reasons for inclusion were resuscitated SD in 7%, recent SD in 8%, and a diagnosis of cardiomyopathy or channelopathy in a living relative in 72%. Also, 13% were athletes. Family trees were constructed and each death's circumstances were recorded. Autopsy and medical records were reviewed., Results: Overall, 18% of SDs occurred during physical exercise, 32% during normal daily activities, and 37% during rest or sleep. There was a significant association between male sex and SD: 111 males (73%) vs. 41 females (27%; P=.03). Exercise-related SD was associated with young age (P=.01). The percentage of SDs associated with exercise, stress or normal daily activities was significantly greater with cardiomyopathy than channelopathy (61% vs. 41%; P=.057). All athletes were male and the majority died during exercise (50% vs. 11% of non-athletes; P=.0002). Patients with Brugada syndrome had the highest percentage of SDs during rest or sleep (i.e. 47%). No clear trigger could be identified in 33%., Conclusions: SD was common in inherited heart disease, which accounted for a significant number of cases. Males clearly predominated over females (ratio 3:1) among SD cases (irrespective of pathological type). Most SDs occurred during exercise or normal daily activities in cardiomyopathies and during rest or sleep in channelopathies. The percentage of exercise-related SDs (i.e. 18%) was higher than expected.

Heavily calcified lesions present a challenge for percutaneous coronary intervention. With rotational atherectomy, it is possible to treat these lesions and paclitaxel-eluting stents (PESs) reduce the risk of restenosis over the long term. This retrospective study investigated clinical outcomes with rotational atherectomy and PESs in 50 consecutive patients with heavily calcified lesions. Mortality and target lesion revascularization at 1 year (median, 14 months; interquartile range, 8.75-25.5 months) were recorded. Some 52% of patients were aged over 70 years, 68% were male, 52% had acute coronary syndrome, 80% had multivessel disease and 44% were receiving abciximab. Two patients died in hospital, three died during follow-up (one cardiac death) and 3 (6%) underwent target lesion revascularization. At 1 year, the survival rate free of cardiac death was 94% and the survival rate free of target lesion revascularization was 94%. These findings demonstrate that the combination of rotational atherectomy and PESs gives excellent results in heavily calcified lesions.

Genetically transmitted cardiomyopathies can affect several members in a family. Identification of high-risk patients could lead to a preventive treatment. We report the results of a 5-year experience of a dedicated clinic. Family screening was offered to 493 consecutive unrelated patients; 2,328 subjects (40 +/- 19 years old, 52% men) were evaluated (mean 4.4 relatives/family). Electrocardiography and echocardiography were performed in all cases; additional tests were indicated depending on the disease. Familial study was recommended because of a proband with hypertrophic cardiomyopathy (HC) in 57%, idiopathic dilated cardiomyopathy (IDC) in 14%, arrhythmogenic right ventricular cardiomyopathy (ARVC) in 2%, left ventricular noncompaction in 2%, Brugada syndrome (BS) in 15%, long QT syndrome (LQTS) in 3%, and other conditions in 6%. Familial disease was confirmed in 164 (39%); 43% with HC, 47% with IDC, 25% with ARVC, 33% with left ventricular noncompaction, 28% with BS, and 30% with LQTS. Two hundred twenty-two (44 +/- 20 years old, 60% men) affected relatives were identified (129 of whom were newly diagnosed). Sixty-four patients were newly diagnosed with HC, 40 with IDC, 2 with ARVC, 5 with left ventricular noncompaction, 14 with BS, and 2 with LQTS, in whom appropriate risk stratification and medication, if needed, were initiated (specific medication in 40, 31.0%). Cardioverter-defibrillator implantation was indicated in 4 relatives for primary prevention. Ninety-two (18.7%) had a family history of sudden death (FHSCD). Consanguinity was rare but significantly associated to a higher percentage of family disease (75.0% vs 38.3%, p = 0.003) and family history of sudden death (42.1% vs 17.8, p <0.001). In conclusion, the prevalence of familial disease in inherited cardiac conditions is high. Systematic familial study identified many asymptomatic affected patients who could benefit from early treatment to prevent complications. Dedicated clinics and multidisciplinary teams are needed for proper screening programs.

A young male individual with diagnosis of heat stroke was admitted unconscious to hospital. Electrocardiogram (ECG) at admission demonstrated typical right bundle branch block and ST-segment elevation in V1 and V2 (coved morphology) diagnostic of Brugada syndrome. Maximal creatine kinase was 10,131 (IU/L); creatine kinase-MB, 15 (IU/L); troponin T, 0.039 ng/mL; and creatinine 1.6, mg/dL. Patient recovered from coma on day 6. Electrocardiogram normalized within the first 24 hours; no arrhythmias were documented. Echocardiogram before discharge was normal. Brugada ECG pattern can express intermittently, and challenge tests with a sodium channel blocker are often required for diagnosis. Ventricular arrhythmias and sudden death occur typically at night or during enhanced vagal activity. Fever has been related to polymorphic ventricular tachycardia particularly in children; nevertheless, prevalence is higher within males in their fourth to fifth decade. Mutations in SCN5A gene encoding a sodium channel can be found in up to 30% of cases. This sodium channel is sensitive to temperature changes. Sequencing of the gene failed to find any abnormality in our patient. A possible role of heat shock proteins in ion channels trafficking to cell membrane has been recently described. Despite diffuse ST-T deviations having been described in patients with heat stroke, localized right precordial leads ST elevation consistent with Brugada syndrome have not been reported. Recognition of typical ECG pattern is of importance because this syndrome is associated to an increased risk of sudden cardiac death.

Background: Patients with indications for oral anticoagulation (OAC) undergoing percutaneous coronary artery stenting (PCI-S) represent a high-risk population for major bleeding complications. Chronic kidney disease (CKD) is also associated with poor outcome after PCI-S. Limited data are available regarding the impact of CKD on the frequency of major bleeding and mortality in this population., Methods: We investigated the influence of CKD on major bleeding and all-cause mortality in patients with indication for OAC who undergo PCI-S. Patients were grouped according to calculated creatinine clearance (CrCl): CrCl > 60 mL/min, (n = 98) and CrCl < or = 60 mL/min, (n = 68). Major bleeding and major adverse vascular events (all-cause mortality, myocardial infarction, repeat revascularization, stent thrombosis, or stroke) were collected during follow-up., Results: We analyzed 166 consecutive patients with indication(s) for OAC (77% men; mean age, 71 years; range, 66 to 76 years) after undergoing PCI-S. CKD was associated with higher risk for major bleeding (hazard ratio [HR], 3.44; 95% confidence interval [CI], 1.50 to 7.93; p = 0.004) and all-cause mortality (HR, 3.50; 95% CI, 1.53 to 7.99; p = 0.003). In multivariate analyses, age > 75 years (HR, 2.75; 95% CI, 1.15 to 6.56; p = 0.023), CKD (HR, 2.59; 95% CI, 1.00 to 6.95; p = 0.049), anemia (HR, 2.36; 95% CI, 1.00 to 5.54; p = 0.049), and triple antithrombotic therapy (HR, 3.29; 95% CI, 1.23 to 8.84; p = 0.018) were independent predictors for major bleeding, whereas age > 75 years (HR, 2.38; 95% CI, 1.03 to 5.59; p = 0.046) and CKD (HR, 2.44; 95% CI, 1.03 to 5.82; p = 0.044) were predictors for all-cause mortality., Conclusion: In this high-risk population, CKD is independently associated with increased major bleeding and all-cause mortality following PCI-S.

Introduction and Objectives: Surgical revascularization is the procedure of choice for unprotected left main coronary artery stenosis, but it may be unsuitable in some patients. We report short- and medium-term outcomes of percutaneous coronary intervention for unprotected left main coronary artery stenosis in a series of patients who were poor candidates for surgery., Patients and Method: Descriptive study of a historic cohort of consecutive patients with unprotected left main coronary artery stenosis who were not candidates for surgery, treated with percutaneous coronary intervention at a single center between April 1999 and December 2003., Results: A total of 83 patients (mean age 72 [9] years) were included. Twenty patients (24%) were in shock on presentation. Surgery was considered unsuitable because of unacceptable surgical risk, poor condition of the distal vessels or comorbid conditions in 61 (73.5%) patients, or acute myocardial infarction in 22 (27%). An intraaortic balloon pump was used in 34 (40%); abciximab in 30 (36%) and stenting in 79 (95%) procedures. The intervention was considered successful in 76 patients (92%). Total in-hospital mortality was 28.9% (55% in patients with acute myocardial infarction and 20% in those without acute myocardial infarction). Median follow-up was 17 months. Average survival was 19.7 (2) months. Eighteen (22%) patients were hospitalized again for a new ischemic event, and 14 (17%) underwent revascularization. In 9 cases (10.8%) a new angioplasty was performed, and in 5 (6.0%) surgical revascularization was necessary., Conclusions: Percutaneous coronary intervention is an option for revascularization in left main coronary artery stenosis in patients who are poor candidates for surgery, although in-hospital and long-term mortality remain high.