A validated capillary microsampling liquid chromatography-tandem mass spectrometry method for quantification of antisense oligonucleotides in mouse serum.

Background: Capillary microsampling (CMS) has been used for quantitative bioanalysis of small molecules; however, there is no report of applying this technique in the bioanalysis of antisense oligonucleotides (ASOs). Results: A CMS liquid chromatography-tandem mass spectrometry method was successfully developed and validated for the quantification of ASO1 in mouse serum. The validated method was applied in a safety study in juvenile mice. Equivalent performance between CMS samples and conventional samples was demonstrated in the mouse study. Conclusion: This work is the first to report using CMS for liquid chromatography-tandem mass spectrometry quantitative bioanalysis of ASOs. The validated CMS method was successfully applied to support good laboratory practice safety studies in mice and the CMS strategy has subsequently been applied to other ASOs.

A Novel Hybridization LC-MS/MS Methodology for Quantification of siRNA in Plasma, CSF and Tissue Samples.

Therapeutic oligonucleotides, such as antisense oligonucleotide (ASO) and small interfering RNA (siRNA), are a new class of therapeutics rapidly growing in drug discovery and development. A sensitive and reliable method to quantify oligonucleotides in biological samples is critical to study their pharmacokinetic and pharmacodynamic properties. Hybridization LC-MS/MS was recently established as a highly sensitive and specific methodology for the quantification of single-stranded oligonucleotides, e.g., ASOs, in various biological matrices. However, there is no report of this methodology for the bioanalysis of double-stranded oligonucleotides (e.g., siRNA). In this work, we investigated hybridization LC-MS/MS methodology for the quantification of double-stranded oligonucleotides in biological samples using an siRNA compound, siRNA-01, as the test compound. The commonly used DNA capture probe and a new peptide nucleic acid (PNA) probe were compared for the hybridization extraction of siRNA-01 under different conditions. The PNA probe achieved better extraction recovery than the DNA probe, especially for high concentration samples, which may be due to its stronger hybridization affinity. The optimized hybridization method using the PNA probe was successfully qualified for the quantitation of siRNA-01 in monkey plasma, cerebrospinal fluid (CSF), and tissue homogenates over the range of 2.00-1000 ng/mL. This work is the first report of the hybridization LC-MS/MS methodology for the quantification of double-stranded oligonucleotides. The developed methodology will be applied to pharmacokinetic and toxicokinetic studies of siRNA-01. This novel methodology can also be used for the quantitative bioanalysis of other double-stranded oligonucleotides.

Validation and application of hybridization liquid chromatography-tandem mass spectrometry methods for quantitative bioanalysis of antisense oligonucleotides.

Background: Antisense oligonucleotide (ASO), an emerging modality in drug research and development, demands accurate and sensitive bioanalysis to understand its pharmacokinetic and pharmacodynamic properties. Results: By combining the advantages of both ligand binding and liquid chromatography-mass spectrometry/tandem mass (LC-MS/MS), hybridization LC-MS/MS methods were successfully developed and validated/qualified in a good lab practice (GLP) environment for the quantitation of an ASO drug candidate in monkey serum, cerebrospinal fluid (CSF) and tissues in the range of 0.5-500 ng/ml. Special treatment of CSF samples was employed to mitigate nonspecific binding, improve long-term storage stability and enable the usage of artificial CSF as a more accessible surrogate matrix. The method was also qualified and applied to ASO quantitation in various monkey tissue samples using a cocktail tissue homogenate as a surrogate matrix. Conclusion: This work was the first reported GLP validation and application of ASO bioanalysis using the hybridization LC-MS/MS platform.

Septal versus apical pacing sites in permanent right ventricular pacing: The multicentre prospective SEPTAL-PM study.

BACKGROUND: The optimal right ventricular pacing site for patients requiring pacemaker implantation for permanent atrioventricular block is a matter of debate. Long-term right ventricular apical pacing has been associated with left ventricular ejection fraction impairment and heart failure. Right ventricular septal pacing has been proposed as an alternative. AIM: The aim of this randomized prospective multicentre trial was to compare left ventricular remodelling and outcomes between right ventricular apical and septal pacing after mid-term follow-up. METHODS: Patients requiring pacemaker implantation for high-degree atrioventricular block were enrolled and randomized in a 1:1 fashion to receive a right ventricular apical or septal lead. RESULTS: A total of 141 patients were included, 69 in the septal group and 72 in the apical group. Both groups exhibited similar left ventricular ejection fractions after 18 months of follow-up (septal 57.1±11.9% vs. apical 57.4±13.4%), and left ventricular ejection fraction variation was similar in the two groups at the end of follow-up (septal -1.5±13.2% vs. apical 0.3±13.3%). Additionally, left ventricular volume, quality of life and 6-minute walk distance were similar in the two groups. However, patients in the septal group were more likely to be asymptomatic, with a significantly lower concentration of N-terminal prohormone of brain natriuretic peptide. Lastly, lead position did not impact 18-month survival. CONCLUSION: Pacing from the right ventricular apex does not have any detrimental effect on left ventricular systolic function compared with septal pacing over an 18-month period.

Evolution of high-grade atrioventricular conduction disorders after transcatheter aortic valve implantation in patients who underwent implantation of a pacemaker with specific mode-that minimizes ventricular pacing-activated.

INTRODUCTION: The evolution of atrioventricular conduction disorders after transcatheter aortic valve implantation (TAVI) remains poorly understood. We sought to identify factors associated with late (occurring ≥7 days after the procedure) high-grade atrioventricular blocks after TAVI, based on specific pacemaker memory data. METHODS AND RESULTS: STIM-TAVI (NCT03338582) was a prospective, multicentre, observational study that enrolled all patients (from November 2015 to January 2017) implanted with a specific dual chamber pacemaker after TAVI, with the SafeR algorithm activated, allowing continuous monitoring of atrioventricular conduction. The primary endpoint was the occurrence of centrally adjudicated late high-grade atrioventricular blocks during the year after TAVI. Among 197 patients, 138 (70.1%) had ≥1 late high-grade atrioventricular block. Whereas oversizing (p = .005), high-grade atrioventricular block during TAVI (p < .001), and early (within 6 days) high-grade atrioventricular block (p < .001) were associated with occurrence of late high-grade atrioventricular block, self-expanding prothesis (p = .88), prior right bundle branch block (p = .45), low implantation (p = .06), and new or wider left bundle branch block and lengthening of PR interval (p = .24) were not. In multivariable analysis, only post-TAVI early high-grade atrioventricular block remained associated with late high-grade atrioventricular blocks (Days 0-1: odds ratio [OR], 3.25; 95% confidence interval [CI], 1.57-6.74; p = .001; Days 2-6: OR, 4.13; 95% CI, 2.06-8.31; p < .001), whereas other conventionally used predictors were not. CONCLUSION: One-third of pacemaker-implanted patients do not experience late high-grade atrioventricular block. Our findings suggest that post-TAVI early high-grade atrioventricular block is the main factor associated with occurrence of late high-grade atrioventricular blocks.

Robustness and relevance of predictive score in sudden cardiac death for patients with Brugada syndrome.

AIMS: Risk stratification of sudden cardiac arrest (SCA) in Brugada syndrome (Brs) remains the main challenge for physicians. Several scores have been suggested to improve risk stratification but never replicated. We aim to investigate the accuracy of the Brs risk scores. METHODS AND RESULTS: A total of 1613 patients [mean age 45 ± 15 years, 69% male, 323 (20%) symptomatic] were prospectively enrolled from 1993 to 2016 in a multicentric database. All data described in the risk score were double reviewed for the study. Among them, all patients were evaluated with Shanghai score and 461 (29%) with Sieira score. After a mean follow-up of 6.5 ± 4.7 years, an arrhythmic event occurred in 75 (5%) patients including 16 SCA, 11 symptomatic ventricular arrhythmia, and 48 appropriate therapies. Predictive capacity of the Shanghai score (n = 1613) and the Sieira (n = 461) score was, respectively, estimated by an area under the curve of 0.73 (0.67-0.79) and 0.71 (0.61-0.81). Considering Sieira score, the event rate at 10 years was significantly higher with a score of 5 (26.4%) than with a score of 0 (0.9%) or 1 (1.1%) (P < 0.01). No statistical difference was found in intermediate-risk patients (score 2-4). The Shanghai score does not allow to better stratify the risk of SCA. CONCLUSIONS: In the largest cohort of Brs patient ever described, risk scores do not allow stratifying the risk of arrhythmic event in intermediate-risk patient.

Age at diagnosis of Brugada syndrome: Influence on clinical characteristics and risk of arrhythmia.

BACKGROUND: Despite a strong genetic background, Brugada syndrome (BrS) mainly affects middle-age patients. Data are scarce in the youngest and oldest age groups. OBJECTIVE: The purpose of this study was to describe the clinical characteristics and variations in rhythmic risk in BrS patients according to age. METHODS: Consecutive BrS patients diagnosed in 15 French tertiary centers in France were enrolled from 1993 to 2016 and followed up prospectively. All of the clinical and ECG data were double reviewed. RESULTS: Among the 1613 patients enrolled (age 45 ± 15 years; 69% male), 3 groups were defined according to age (52 patients <17 years; 1285 between 17 and 59 years; and 276 >60 years). In the youngest patients, we identified more female gender (42%), diagnosis by familial screening (63%), previous sudden cardiac death (15%), SCN5A mutation (62%) sinus dysfunction (8%) and aVR sign (37%) (P <.001). The oldest patients had the same clinical characteristics except for gender (40% women; P <.001). During median follow-up of 5.5 [2.1, 10.0] years, 91 patients experienced an arrhythmic event, including 7 (13%) in the youngest patients, 80 (6%) in middle-age patients, and 4 (1%) in the oldest patients. Annual event rates were 2.1%, 1%, and 0.3%, respectively (P <.01). CONCLUSION: Age on diagnosis changes the clinical presentation of BrS. Although children are identified more during familial screening, they present the highest risk of sudden cardiac death, which is an argument for early and extensive familial screening. The oldest patients present the lowest risk of SCD.

Number of electrocardiogram leads in the diagnosis of spontaneous Brugada syndrome.

BACKGROUND: The recently recommended single lead-based criterion for the diagnosis of Brugada syndrome may lead to overdiagnosis of this disorder and overestimation of the risk of sudden cardiac death. AIM: To investigate the value of a single-lead diagnosis in patients with Brugada syndrome and a spontaneous type 1 electrocardiogram. METHODS: Consecutive patients with Brugada syndrome were included in a multicentre prospective registry; only those with a spontaneous type 1 electrocardiogram were enrolled. Clinical and electrocardiogram data were reviewed by two physicians blinded to the patients' clinical and genetic status. RESULTS: Among 1613 patients, 505 (31%) were enrolled (79% male; mean age 46±15 years). A spontaneous type 1 electrocardiogram pattern was found in one lead in 250 patients (group 1), in two leads in 227 patients (group 2) and in three leads in 27 patients (group 3). Groups were similar except for individuals in group 3, who presented more frequently a fragmented QRS complex, an early repolarization pattern and a prolonged Tpeak-Tend interval. After a mean follow-up of 6.4±4.7 years, ventricular arrhythmia, sudden cardiac death or implantable cardiac defibrillator shock occurred in 46 (9%) patients, without differences between groups. CONCLUSION: The prognosis of Brugada syndrome with a spontaneous type 1 electrocardiogram pattern does not appear to be affected by the number of leads required for the diagnosis.

Incorporating a Physical Activity Program into an Assertive Community Treatment Team: Impact and Strategies.

The objective of this brief report is to present an overview of the main benefits and key characteristics of an individualized physical activity program delivered by an assertive community treatment team in Ottawa, Canada. A mixed-method case study was conducted over a 9-month period. Findings revealed significant reductions in weight, BMI and waist circumference (p < .05) and improvements in self-esteem, autonomy, socialization and other health behaviors. Key characteristics of the program included building a relationship of trust with clients and deploying active efforts to eliminate barriers to PA engagement. Results offer preliminary evidence for integrating an individualized PA program into the ACT team model.

External Validation and Updating of the Cardiac Surgery Score for Prediction of Mortality in a Cardiac Surgery Intensive Care Unit.

OBJECTIVE: To externally validate the predictive performance of the logistic and additive Cardiac Surgery Score (CASUS), a postoperative severity of illness score designed specifically for prediction of mortality in the cardiac surgery intensive care unit. DESIGN: A retrospective analysis of prospectively collected data between July 1, 2012, and September 30, 2015. SETTING: Single university cardiac surgery intensive care unit in Canada. PARTICIPANTS: Consecutive adult patients (n = 4,519) admitted to the intensive care unit after cardiac surgery. INTERVENTION: None. MEASUREMENTS AND MAIN RESULTS: The mortality predicted by logistic CASUS was calculated for each patient on admission day 0 and postoperative days 2, 4, 7, and 10 using the original model equation. The mortality predicted by additive CASUS was determined on each day with separate logistic regression models, using the total score as a single variable. The observed mortality was 1.8%. Logistic CASUS overestimated mortality by 78%, 59%, 51%, 52%, and 29% on days 0, 2, 4, 7, and 10, respectively. After model updating with logistic calibration, logistic CASUS consistently provided estimates of death comparable with the observed mortality, as determined with the Hosmer-Lemeshow goodness-of-fit test. The stability of those estimates was confirmed by bootstrapping. Similar calibration results were obtained with additive CASUS. Logistic and additive CASUS had good discrimination with areas under the receiver operating characteristic curve greater than 0.7 on each study day. CONCLUSIONS: Recalibrated logistic CASUS reliably predicts mortality in the intensive care unit after cardiac surgery. Logistic regression models derived from additive CASUS perform as well as logistic CASUS.

Ischemic and bleeding outcomes after coronary artery bypass grafting among patients initially treated with a P2Y12 receptor antagonist for acute coronary syndromes: Insights on timing of discontinuation of ticagrelor and clopidogrel prior to surgery.

BACKGROUND: Clinical outcomes in acute coronary syndrome patients treated with P2Y12 inhibitors who require urgent coronary artery bypass grafting (CABG) have not been well studied. METHODS: We examined clinical outcomes in acute coronary syndrome patients in relation to the timing of CABG following P2Y12 inhibitor discontinuation (<72 h, 72 h to five days, >5 days). The primary ischemic outcome was a composite of death, reinfarction, need for revascularization, or stroke. The primary safety outcome was bleeding of at least moderate severity as defined by a Universal Definition of Perioperative Bleeding class ≥2. RESULTS: Among 508 patients (95 ticagrelor, 413 clopidogrel), the timing of CABG following P2Y12 inhibitor discontinuation was <72 h in 32.1%, 72 h to five days in 23.2% and >5 days in 44.7%. Compared with CABG within 72 h, CABG 72 h to five days (adjusted odds ratio (OR) 0.35; 95% confidence interval (CI) 0.14-0.85; p=0.02) but not >5 days (adjusted OR 0.62; 95% CI 0.33-1.16; p=0.14) after P2Y12 inhibitor discontinuation was associated with lower odds of the primary ischemic outcome. Compared with CABG within 72 h, CABG 72 h to five days (adjusted OR 0.38; 95% CI 0.22-0.66; p=0.001) and >5 days (adjusted OR 0.33; 95% CI 0.20-0.53; p<0.001) after P2Y12 inhibitor discontinuation were associated with lower rates of Universal Definition of Perioperative Bleeding class ≥2 bleeding. CONCLUSIONS: CABG within 72 h after P2Y12 inhibitor discontinuation is associated with excess ischemia and bleeding. The rates of ischemic and bleeding events were comparable in patients undergoing CABG 72 h to five days compared with >5 days after P2Y12 inhibitor discontinuation.

Clinical presentation and follow-up of women affected by Brugada syndrome.

BACKGROUND: Studies in Brugada syndrome (BrS) have mainly consisted of men. OBJECTIVE: The purpose of this study was to describe the clinical characteristics and arrhythmic risk factors in BrS women. METHODS: Consecutive BrS patients were enrolled from 1993 and followed prospectively. RESULTS: Among 1613 patients, 494 were women (mean age 47 ± 16 years). Women were more frequently asymptomatic than men (423 [86%] vs 867 [77%], respectively; P = .001) and less frequently had a spontaneous ECG pattern (107 [22%] vs 398 [36%], respectively; P <.001). During median [25th, 75th percentile] follow-up of 57 [23, 118] vs 62 [22, 113] months (P = .65), arrhythmic events occurred in 12 women (2%) vs 79 men (7%) (P = .0005). Mean age at the first event was 48.6 ± 17.8 years for women vs 43 ± 14.2 years for men (P <.001). Gender was significantly related to cardiac events (hazard ratio [HR] 2.96; 95% confidence interval [CI] 1.6-5.4; P = .0005). In multivariate analysis, event predictors in women were index patient status (HR 10.15; 95% CI 1.7-61.4; P = .01), previous sudden cardiac death (HR 69.4; 95% CI 15-312.5; P <.0001), syncope (HR 6.8; 95% CI 1.4-34.5; P = .02), fragmented QRS (HR 20.2; 95% CI 1.8-228.9; P = .02), and QRS duration >120 ms (HR 4.7; 95% CI 1.2-19.5; P = .03). CONCLUSION: Women represent a lower-risk group than men among individuals with BrS. In asymptomatic women, fragmented QRS and QRS >120 ms seem to be the only event predictors.

[Physical activity programs and severe mental illness: A case study of an Assertive Community Treatment (ACT) team]. / Programme d'activité physique et troubles graves de santé mentale : étude de cas d'une équipe communautaire de traitement intensif (ÉCTI).

Context : As a therapeutic intervention, physical activity has the potential to improve the quality of life of individuals with severe mental illnesses.Objectives : The goal of this case study was to conduct an in-depth examination of an individualized physical activity program for patients suffering from severe mental illnesses that was implemented by an Assertive Community Treatment (ACT) team in Ottawa, Canada.Method : Using a mixed-methods design, physical health parameters were measured over a nine-month period and semi-structured interviews were conducted with fourteen patients and five staff members.Results : The findings showed a significant reduction in weight following the evaluation period, as well as positive effects in terms of patients' self-esteem, autonomy, and socialization. The quality of the therapeutic relationship, the elimination of barriers, and the continued involvement of staff members were some of the key characteristics that led to the program's success.Discussion/conclusion : These promising results are an indication of the feasibility of this type of intervention among patients with severe mental illnesses as a therapeutic approach to improve their quality of life and support their recovery and social integration.

Utility of Novel Cardiorenal Biomarkers in the Prediction and Early Detection of Congestive Kidney Injury Following Cardiac Surgery.

Acute Kidney Injury (AKI) in the context of right ventricular failure (RVF) is thought to be largely congestive in nature. This study assessed the utility of biomarkers high sensitivity cardiac troponin T (hs-cTnT), N-Terminal Pro-B-Type Natriuretic Peptide (NT-proBNP), and neutrophil gelatinase-associated lipocalin (NGAL) for prediction and early detection of congestive AKI (c-AKI) following cardiac surgery. This prospective nested case-control study recruited 350 consecutive patients undergoing elective cardiac surgery requiring cardiopulmonary bypass. Cases were patients who developed (1) AKI (2) new or worsening RVF, or (3) c-AKI. Controls were patients free of these complications. Biomarker levels were measured at baseline after anesthesia induction and immediately postoperatively. Patients with c-AKI had increased mean duration of mechanical ventilation and length of stay in hospital and in the intensive care unit (p < 0.01). For prediction of c-AKI, baseline NT-proBNP yielded an area under the curve (AUC) of 0.74 (95% CI, 0.60⁻0.89). For early detection of c-AKI, postoperative NT-proBNP yielded an AUC of 0.78 (0.66⁻0.91), postoperative hs-cTnT yielded an AUC of 0.75 (0.58⁻0.92), and ∆hs-cTnT yielded an AUC of 0.80 (0.64⁻0.96). The addition of baseline creatinine to ∆hs-cTnT improved the AUC to 0.87 (0.76⁻0.99), and addition of diabetes improved the AUC to 0.93 (0.88⁻0.99). Δhs-cTnT alone, or in combination with baseline creatinine or diabetes, detects c-AKI with high accuracy following cardiac surgery.

Efficacy of bendamustine and rituximab in splenic marginal zone lymphoma: results from the phase II BRISMA/IELSG36 study.

Splenectomy in addition to immunotherapy with rituximab can provide quick and sometimes durable disease control in patients with splenic marginal zone lymphoma (SMZL). However, systemic chemotherapy is ultimately required in many cases. The BRISMA (Bendamustine-rituximab as first-line treatment of splenic marginal zone lymphoma)/IELSG (International Extranodal Lymphoma Study Group)36 trial is an open-label, single arm phase II study designed by the IELSG in cooperation with the Fondazione Italiana Linfomi and the lymphoma Study Association according to Simon's two-stage method. The primary endpoint was complete response rate. Fifty-six patients with SMZL diagnosis confirmed on central revision were treated with bendamustine (90 mg/m2  days 1, 2) and rituximab (375 mg/m2  day 1) every 28 days for six cycles (B-R). The overall response and CR rates were 91% and 73%, respectively. Duration of response, progression-free survival and overall survival at 3 years were 93% (95% confidence interval [CI] 81-98), 90% (95% CI 77-96) and 96% (95% CI 84-98), respectively. Toxicity was mostly haematological. Neutropenia grade ≥3 was recorded in 43% of patients; infections and febrile neutropenia in 5·4% and 3·6%. Overall, 14 patients (25%) experienced serious adverse events. Five patients (9%) went off-study because of toxicity and one patient died from infection. In conclusion, B-R resulted in a very effective first-line regimen for SMZL. Based on the results achieved in the BRISMA trial, B-R should be considered when a chemotherapy combination with rituximab is deemed necessary for symptomatic SMZL patients.

Association of Frailty and Long-Term Survival in Patients Undergoing Coronary Artery Bypass Grafting.

BACKGROUND: Frailty is increasing in prevalence and poses a formidable challenge for clinicians. The cardiac surgery literature consists primarily of small single-center studies with limited follow-up, and the epidemiological features of frailty remain to be elucidated in long-term follow-up. METHODS AND RESULTS: We conducted a population-based, retrospective, cohort study in Ontario, Canada, between 2008 and 2015. Frailty was defined using the Johns Hopkins Adjusted Clinical Groups frailty indicator (a multidimensional instrument validated for research using administrative data). The primary outcome was mortality. Mortality rates were calculated using the Kaplan-Meier method. The hazard of death was assessed using a multivariable Cox proportional hazard model. Of 40 083 patients, 8803 (22%) were frail. At 4±2 years of follow-up, age- and sex-standardized mortality rate per 1000 person-years was higher in frail (33; 95% confidence interval, 29-36) compared with nonfrail (22; 95% confidence interval, 19-24) patients. Frailty was associated with an increased risk of long-term mortality (adjusted hazard ratio, 1.20; 95% confidence interval, 1.12-1.28) and greater differences in the survival of patients between 40 and 74 years of age than in those who were ≥85 years old. CONCLUSIONS: Frailty was present in a large proportion of patients undergoing coronary artery bypass grafting and was independently associated with long-term mortality. The adjusted risk of frailty-related death was inversely proportional to age. Our findings highlight the need for more comprehensive preoperative risk stratification models to assist with optimal selection of operative candidates. In addition, we identified the <75 years age group as a potential target for comprehensive preoperative optimization programs, such as cardiac prehabilitation, nutritional augmentation, and psychosocial support.

Long-term prognostic significance of right bundle-branch morphology ventricular ectopy induced during stress test in patients with intermediate to high probability of coronary artery disease.

Aims: Stress-induced right bundle-branch block morphology ventricular ectopy (SI-RBVE) may be caused by left ventricular myocardial anomalies. While frequent ventricular ectopy (FVE) has been linked to poor outcomes, the prognostic value of SI-RBVE has not been established. The study aims to determine whether SI-RBVE is associated with increased mortality. Methods and results: Three hundred forty-three patients with an intermediate to high probability of coronary artery disease were prospectively included. Patients were referred for a single-photon emission computed tomography and underwent a stress test according to standard protocols. Stress-induced right bundle-branch block morphology ventricular ectopy (VE) was defined as one or more induced premature beats with positive predominance in V1. Frequent VE was defined as the presence of seven or more ventricular premature beats per minute or any organized ventricular arrhythmia. During a mean follow-up of 4.5 ± 1.3 years, 59 deaths occurred. The death rate was higher in the SI-RBVE group (23.4% vs. 14.0%, P = 0.021). Age [odds ratio (OR) = 1.09 (95% CI: 1.06-1.13), P < 0.001] and peripheral artery disease [OR = 2.47 (95% CI: 1.35-4.50) P = 0.003] were independent factors of mortality, but single-photon emission computed tomography findings were not. There was an interaction between SI-RBVE and left ventricular ejection fraction (LVEF). In patients with LVEF > 50%, SI-RBVE was an incremental risk factor for mortality [OR = 2.83 (95% CI: 1.40-5.74), P = 0.004]. Stress-induced right bundle-branch block morphology VE patients also presented higher rates of known coronary artery disease, ischaemia, scar, and ST-segment changes. Frequent VE was not related to mortality. Conclusion: Stress-induced right bundle-branch block morphology VE is associated with an increased mortality in patients with preserved LVEF.

Prospective External Validation of Three Preoperative Risk Scores for Prediction of New Onset Atrial Fibrillation After Cardiac Surgery.

BACKGROUND: Postoperative atrial fibrillation (POAF) is associated with early and late morbidity and mortality of cardiac surgical patients. Prophylactic treatment of atrial fibrillation (AF) has been recommended to improve outcome in cardiac surgical patients at high risk of developing POAF. Reliable models for prediction of POAF are needed to achieve that goal. This study attempted to externally validate 3 risk models proposed for preoperative prediction of POAF in cardiac surgical patients: the POAF score, the CHA2DS2-VASc score, and the Atrial Fibrillation Risk Index. METHODS: This was a prospective cohort study of 1416 adult patients who underwent nonemergent coronary artery bypass graft and/or valve surgery in a single cardiac surgical center between February 2014 and September 2015. A risk score for each of the 3 prediction models was calculated in each patient. All patients were followed for up to 2 weeks, or until hospital discharge, to observe the primary outcome of new onset AF requiring treatment. Discrimination was assessed using receiver operating characteristic curves. Calibration was assessed using the Pearson χ goodness-of-fit test and calibration plots. Utility of the score to implement AF prophylaxis based on the risk of POAF, in comparison to strategies of treating all patients, or not treating any patients, was assessed via a net benefit analysis. RESULTS: Of the 1416 patients included in this study, 478 had the primary outcome (33.8%). The areas under the receiver operating characteristic curve for prediction of POAF in the population subsets for which the scores were validated were as follows: 0.651 (95% confidence interval [CI], 0.621-0.681) for the POAF score, 0.593 (95% CI, 0.557-0.629) for the CHA2DS2-VASc score (P < .001 versus POAF score, P < .222 versus Atrial Fibrillation Risk Index), and 0.563 (95% CI, 0.522-0.604) for the Atrial Fibrillation Risk Index (P < .001 versus POAF score). The calibration analysis showed that the predictive models had a poor fit between the observed and expected rates of POAF. Net benefit analysis showed that AF preventive strategies based on these scores, and targeting patients with moderate or high risk of POAF, improve decision-making in comparison to preventive strategies of treating all patients. CONCLUSIONS: The 3 prediction scores evaluated in this study have limited ability to predict POAF in cardiac surgical patients. Despite this, they may be useful in preventive strategies targeting patients with moderate or high risk of PAOF in comparison with preventive strategies applied to all patients.

Sodium-channel blocker challenge in the familial screening of Brugada syndrome: Safety and predictors of positivity.

BACKGROUND: Sodium-channel blocker challenge (SCBC) is frequently performed to unmask Brugada syndrome. OBJECTIVE: We aim to identify predictors of positivity and complications of SCBC in the setting of familial screening of Brugada syndrome. METHODS: All consecutive patients from 2000 to 2014 who benefit from a sodium-channel blocker and belong to a family with at least 2 subjects affected by the syndrome were enrolled and followed prospectively. Data were reviewed by 2 physicians blinded to the clinical and genetic status. RESULTS: Of the 672 SCBCs performed in 137 families, 337 (50%) were positive. Multivariate analysis identified ajmaline (odds ratio [OR] 2.98; 95% CI 1.65-4.91) and a significant S wave in lead DII (OR 3.11; 95% CI 2.12-4.58), DIII (OR 2.75; 95% CI 1.78-4.25), or V5 (OR 3.71; 95% CI 2.54-5.44) as predictors of a positive SCBC (P < .0001). Eleven patients (1.6%) presented complications (10 ventricular arrhythmias and 1 atrial flutter), but no deaths occurred. Familial history of complications (OR 41; lower quartile, upper quartile 10, 203; P < .0001), young age (P = .04), and decreased electrocardiographic conduction parameters at baseline (P = .04) were predictors of complications. QRS enlargement during SCBC was not associated with complications. During a median follow-up of 106 months (lower quartile, upper quartile 54, 143 months), 11 life-threatening arrhythmias occurred. CONCLUSION: SCBC in the screening of familial Brugada syndrome is safe. The risk of complication is considerably increased in the case of familial history of complicated SCBC, in young patients, and in the presence of decreased electrocardiographic conduction parameters. However, QRS enlargement during the test is not directly related to complications and should not be used to prematurely stop the test unless leading to false-negative results.