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.

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.

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.

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.

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.

[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.

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.

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.

Predicting New-Onset Postoperative Atrial Fibrillation in Cardiac Surgery Patients.

OBJECTIVE: To derive a simple clinical prediction rule identifying patients at high risk of developing new-onset postoperative atrial fibrillation (POAF) after cardiac surgery. DESIGN: Retrospective analysis on prospectively collected observational data. SETTING: A university-affiliated cardiac hospital. PARTICIPANTS: Adult patients undergoing coronary artery bypass grafting and/or valve surgery. INTERVENTIONS: Observation for the occurrence of new-onset postoperative atrial fibrillation. MEASUREMENTS AND MAIN RESULTS: Details on 28 preoperative variables from 999 patients were collected and significant predictors (p<0.2) were inserted into multivariable logistic regression and reconfirmed with recursive partitioning. A total of 305 (30.5%) patients developed new-onset POAF. Eleven variables were associated significantly with atrial fibrillation. A multivariable logistic regression model included left atrial dilatation, mitral valve disease, and age. Coefficients from the model were converted into a simple 7-point predictive score. The risk of POAF per score is: 15.0%, if 0; 20%, if 1; 27%, if 2; 35%, if 3; 44%, if 4; 53%, if 5; 62%, if 6; and 70%, if 7. A score of 4 has a sensitivity of 44% and a specificity of 82% for POAF. A score of 6 has a sensitivity of 11% and a specificity of 97%. Bootstrapping with 5,000 samples confirmed the final model provided consistent predictions. CONCLUSIONS: This study proposed a simple predictive score incorporating three risk variables to identify cardiac surgical patients at high risk of developing new-onset POAF. Preventive treatment should target patients ≥ 65 years with left atrial dilatation and mitral valve disease.

Off-label use of recombinant activated factor VII in surgical and non-surgical patients at 16 Canadian hospitals from 2007 to 2010 (Canadian Registry Report).

PURPOSE: Recombinant activated factor VII (rFVIIa) is a pro-hemostatic drug that is approved for treatment of bleeding in hemophilia patients, but it is frequently used off-label in non-hemophiliacs. The purpose of this study was to determine if the off-label use of rFVIIa is expanding and whether this poses a net harm to patients. METHODS: For this historical cohort study, data were collected on all non-hemophilia patients who received rFVIIa from 2007 to 2010 at 16 Canadian centres, and the pattern of use was examined. Logistic regression was used to determine the prognostic importance of severity of bleeding and the presence of an rFVIIa dose-effect relationship with major adverse events. RESULTS: One thousand three hundred seventy-eight patients received rFVIIa off-label, and 987 (72%) of these patients underwent cardiac surgery. The median [interquartile range] dose was 57 [36-85] µg·kg(-1). Usage increased from 2007 to 2008 (n = 341 and 380, respectively) but decreased in 2009 and 2010 (n = 350 and 307, respectively). Dose of rFVIIa and bleeding severity were associated with measured adverse events (P < 0.05). After adjusting for bleeding severity, dose was not associated with any of the adverse events. CONCLUSIONS: The off-label use of rFVIIa in Canada remains stable. Since severity of bleeding is prognostically important, the benefits of rapidly gaining control of bleeding that is non-responsive to conventional therapies may at times warrant the use of potent hemostatic drugs with established risk profiles, such as rFVIIa.

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.

First inappropriate implantable cardioverter defibrillator therapy is often due to inaccurate device programming: analysis of the French OPERA registry.

AIMS: Inappropriate therapy delivered by implantable cardioverter defibrillators (ICDs) remains a challenge. The OPERA registry measured the times to, and studied the determinants of, first appropriate (FAT) and inappropriate (FIT) therapies delivered by single-, dual- and triple-chamber [cardiac resynchronization therapy defibrillator (CRT-D)] ICD. METHODS AND RESULTS: We entered 636 patients (mean age = 62.0 ± 13.5 years; 88% men) in the registry, of whom 251 received single-, 238 dual-, and 147 triple-chamber ICD, for primary (30.5%) or secondary (69.5%) indications. We measured times to FAT and FIT as a function of multiple clinical characteristics, examined the effects of various algorithm components on the likelihood of FAT and FIT delivery, and searched for predictors of FAT and FIT. Over 22.8 ± 8.8 months of observation, 184 patients (28.9%) received FAT and 70 (11.0%) received FIT. Ventricular tachycardia (VT) was the trigger of 88% of FAT, and supraventricular tachycardia was the trigger of 91% of FIT. The median times to FIT (90 days; range 49-258) and FAT (171 days; 50-363) were similar. The rate of FAT was higher (P <0.001) in patients treated for secondary than primary indications, while that of FIT were similar in both groups. Out of 57 analysable FIT, 27 (47.4%) could have been prevented by fine tuning the device programming like the sustained rate duration or the VT discrimination algorithm. CONCLUSIONS: First inappropriate therapy occurred in 11% of 636 ICD recipients followed for ∼2 years. Nearly 50% of FIT could have been prevented by improving device programming.

Near elimination of ventricular pacing in SafeR mode compared to DDD modes: a randomized study of 422 patients.

AIMS: SafeR performance versus DDD/automatic mode conversion (DDD/AMC) and DDD with a 250-ms atrioventricular (AV) delay (DDD/LD) modes was assessed toward ventricular pacing (Vp) reduction. METHODS: After a 1-month run-in phase, recipients of dual-chamber pacemakers without persistent AV block and persistent atrial fibrillation (AF) were randomly assigned to SafeR, DDD/AMC, or DDD/LD in a 1:1:1 design. The main endpoint was the percentage of Vp (%Vp) at 2 months and 1 year after randomization, ascertained from device memories. Secondary endpoints include %Vp at 1 year according to pacing indication and 1-year AF incidence based on automatic mode switch device stored episodes. RESULTS: Among 422 randomized patients (73.2±10.6 years, 50% men, sinus node dysfunction 47.4%, paroxysmal AV block 30.3%, bradycardia-tachycardia syndrome 21.8%), 141 were assigned to SafeR versus 146 to DDD/AMC and 135 to DDD/LD modes. Mean %Vp at 2 months was 3.4±12.6% in SafeR versus 33.6±34.7% and 14.0±26.0% in DDD/AMC and DDD/LD modes, respectively (P<0.0001 for both). At 1 year, mean %Vp in SafeR was 4.5±15.3% versus 37.9±34.4% and 16.7±28.0% in DDD/AMC and DDD/LD modes, respectively (P<0.0001 for both). The proportion of patients in whom Vp was completely eliminated was significantly higher in SafeR (69%) versus DDD/AMC (15%) and DDD/LD (45%) modes (P<0.0001 for both), regardless of pacing indication. The absolute risk of developing permanent AF or of remaining in AF for >30% of the time was 5.4% lower in SafeR than in the DDD pacing group (ns). CONCLUSIONS: In this selected patient population, SafeR markedly suppressed unnecessary Vp compared with DDD modes.

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.

Acute kidney injury after cardiac surgery: focus on modifiable risk factors.

BACKGROUND: Acute kidney injury (AKI) after cardiac surgery is a major health issue. Lacking effective therapies, risk factor modification may offer a means of preventing this complication. The objective of the present study was to identify and determine the prognostic importance of such risk factors. METHODS AND RESULTS: Data from a multicenter cohort of 3500 adult patients who underwent cardiac surgery at 7 hospitals during 2004 were analyzed (using multivariable logistic regression modeling) to determine the independent relationships between 3 thresholds of AKI (>25%, >50%, and >75% decrease in estimated glomerular filtration rate within 1 week of surgery or need for postoperative dialysis) with death rates, as well as to identify modifiable risk factors for AKI. The 3 thresholds of AKI occurred in 24% (n=829), 7% (n=228), and 3% (n=119) of the cohort, respectively. All 3 thresholds were independently associated with a >4-fold increase in the odds of death and could be predicted with several perioperative variables, including preoperative intra-aortic balloon pump use, urgent surgery, and prolonged cardiopulmonary bypass. In particular, 3 potentially modifiable variables were also independently and strongly associated with AKI. These were preoperative anemia, perioperative red blood cell transfusions, and surgical reexploration. CONCLUSIONS: AKI after cardiac surgery is highly prevalent and prognostically important. Therapies aimed at mitigating preoperative anemia, perioperative red blood cell transfusions, and surgical reexploration may offer protection against this complication.

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.

Relationship between amplitude and timing of heart sounds and endocardial acceleration.

OBJECTIVE: To study the correlation between heart sounds and peak endocardial acceleration (PEA) amplitudes and timings, by modulation of paced atrioventricular (AV) delay in recipients of dual chamber pacemakers. METHODS: Ten recipients of dual chamber pacemakers implanted for high-degree AV block were studied. Endocardial acceleration (EA) and phonocardiographic and electrocardiographic signals were recorded during performance of an AV delay scan in VDD and DDD modes. RESULTS: First PEA (PEA I) and first heart sound (S1) changed similarly with the AV delay. A close intrapatient correlation was observed between S1 and PEA I amplitudes in all patients (P < 0.0001). The interpatient normalized PEA I to S1 amplitudes correlation was r = 0.89 (P < 0.0001) in DDD mode, and r = 0.81 (P < 0.0001) in VDD mode. The mean cycle-by-cycle PEA I to S1 delay was -4.3 +/- 22 ms and second PEA (PEA II) to second heart sound (S2) delay was -7.7 +/- 15 ms. CONCLUSIONS: A close correlation was observed between PEA I and S1 amplitudes and timings, and between PEA II and S2 timings. These observations support the hypothesis that PEA and heart sounds are manifestations of the same phenomena. EA might be a useful tool to monitor cardiac function.